Pharmaceutically active pyrrolidine derivatives as Bax inhibitors

ABSTRACT

The present invention is related to new substituted pyrrolidine derivatives of formula (I). Said compounds are preferably for use as pharmaceutically active compounds. Specifically, pyrrolidine derivatives of formula (I) are useful in the treatment and/or prevention of neurodegenerative disorders, diseases associated with polygultamine tracts, epilepsy, ischemia, infertility, cardiovascular disorders renal hypoxia, hepatitis and AIDS. Said pyrrolidine derivatives display a modulatory and most notably a down-regulating-up to an inhibitory-activity with respect to the cellular death agonist Bax and/or the activation pathways leading to Bax and allows therefore to block the release of cytochrome (c). The present invention is furthermore related to novel pharmaceutically activity substituted pyrrolidine derivatives as well as to methods of their preparation, wherein X is selected from the group consisting of O, S, CR&lt;6&gt;R&lt;7&gt;, NOR&lt;6&gt;, NNR&lt;6&gt;R&lt;7&gt;; A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO2—, —SO2NH—; —CH2—; B is either a group —(C═O)—NR&lt;8&gt;R&lt;9&gt; or represents a heterocyclic residue having the formula (II) wherein Q is NR&lt;10&gt;, O or S; n is an integer selected of 0, 1 or 2; Y, Z and E form together with the 2 carbons to which they are attached a 5–6 membered aryl or heteroaryl ring.

FIELD OF THE INVENTION

The present invention is related to new substituted pyrrolidinederivatives of formula I. Said compounds are preferably for use aspharmaceutically active compounds. Specifically, pyrrolidine derivativesof formula I are useful in the treatment and/or prevention ofneurodegenerative disorders, diseases associated with polyglutaminetracts, epilepsy, ischemia, infertility, cardiovascular disorders, renalhypoxia, hepatitis and AIDS. Said pyrrolidine derivatives display amodulatory and most notably a down-regulating—up to aninhibitory—activity with respect to the cellular death agonist Baxand/or the activation pathways leading to Bax and allows therefore toblock the release of cytochrome c. The present invention is furthermorerelated to novel pharmaceutically active substituted pyrrolidinederivatives as well as to methods of their preparation.

BACKGROUND OF THE INVENTION

Apoptosis denotes the complex contortions of the membrane and organellesof a cell as it undergoes the process of programmed cell death. Duringsaid process, the cell activates an intrinsic suicide program andsystematically destroys itself in a controlled manner or by aself-regulated process. The following series of events can be observed:

-   -   The cell surface begins to bleb and expresses pro-phagocytic        signals. The whole apoptotic cell then fragments into        membrane-bound vesicles that are rapidly and neatly disposed of        by phagocytosis, so that there is minimal damage to the        surrounding tissue.    -   The cell then separates from its neighbors.    -   The nucleus also goes through a characteristic pattern of        morphological changes as it commits genetic suicide. The        chromatin condenses and is specifically cleaved to fragments of        DNA.

Neuronal cell death plays an important role in ensuring that the nervoussystem develops normally. It appears that the death of developingneurons depends on the size of the target that they innervate: cellswith fewer synaptic partners are more likely to die than those that haveformed multiple synapses. This may reflect a process, which balances therelative number of pre- to postsynaptic neurons in the developingnervous system. Although neuronal cell death was assumed to beapoptotic, it was only recently that neurons in developing rodent brainwere conclusively shown to undergo apoptosis as classified by morphologyand DNA fragmentation.

Neuronal death occurs via either apoptotic or necrotic processesfollowing traumatic nerve injury or during neurodegenerative diseases.Multiple components are emerging as key players having a role in drivingneuronal programmed cell death. Amongst the components leading toneuronal apoptosis are protein members belonging to the Bcl-2 family(see Jacobson, M. D. 1997. Current Biology 7:R 277–R281; Kroemer, G. C.1997. Nature Medicine: 614–620; Reed, J. C. 1997. Nature 387:773–776).

The entire Bcl-2 family comprises both anti-apoptotic (Bcl-2, Bcl-x_(L),Bcl-w, Mcl-1, A1, NR-13, BHRF1, LMW5-HL, ORP16, KS-Bcl-2, E1B-19K,CED-9) and pro-apoptotic (Bax, Bak, Bok, Bik, Blk, Hrk, BNIP3, Bim_(L),Bad, Bid, EGL-1) molecules (see Kelekar, A., and C. B. Thomp-son 1998.Trends in Cell Biology 8:324–330). The specific member thereof, i.e. thefirst found, Bcl-2 is a 26 kDa protein that localizes to themitochondrial, endoplasmatic reticulum and perinuclear membranes. TheBcl-2 family proteins can form homo- and hetero-dimers that involveamino acid sequences known as Bcl-2 homology (BH) domains. So far, fourof said domains (BH1 to 4) have been identified, the BH3 having beenattributed a particularly prominent role in view of the death-promotingcascade. Said BH3 domain of the pro-apoptotic members appears to berequired for the interaction between anti and pro-apoptotic molecules.The principal site of action of some of the Bcl-2 family members seemsto be the mitochondria. Mitochondria have been shown to play a majorrole in many types of apoptosis. In particular, this organelle has beenshown to release Apoptosis Inducing Factor and cytochrome c, ahemoprotein which is bound to the outer surface of the innermitochondrial membrane. Said cytochrome c has been shown to triggercaspase 9 activation through Apaf-1/caspase 9 complex formation. Bcl-2family members play a key role in regulating cytochrome c release. WhileBcl-2 and Bcl-x_(L) have been shown to suppress cytochrome c release,Bax has been found to stimulate this event both in vitro using isolatedmitochondria as well as in intact cells following heterologousexpression (Martinou et al.; The Journal of Cell Biology, 128, 1995,201–208). The mechanisms by which these proteins perform their functionare currently unknown. The three-dimensional structure of Bcl-xL and Bidrevealed structural similarities between these proteins and thechannel-forming domains of the bacterial toxins colicins and diphtheriatoxins. Consistent with such structural similarity, some members of thisfamily including Bax were also found able to form ion channels insynthetic lipid membranes.

Studies performed with Bax-deficient mice led to the conclusion that Baxplays a promi-nent role within the apoptosis pathways, notably inneuronal apoptosis. Bax is viewed to be essential for apoptosis inducedby NGF deprivation in neonatal sympathetic neurons or for apoptosisinduced in cerebellar granule cells by potassium deprivation from theculture medium. Moreover, it was found that in the Bax-deficient mice(knock-out) neonatal moto-neurons from the facial nucleus can survivefollowing axotomy (see Deckwerth, T. L., Elliott J. L., Knudson C. M. etal. 1996. Neuron 17,401–41). Hence, the inhibition of the Bax activityleading to the prevention of cytochrome c release from mitochondriaduring apoptosis, is viewed to be useful to protect neurons and alsoother cell types from various cell death stimuli.

In WO 97/01635 (Neurex Corp.) the inhibition of apoptosis in an effortto promote cell survival is suggested to be achieved by introducing intothe cell a chimeric gene containing a polynucleotide encoding aBax-ω-polypeptide (a splice variant of the Bax gene, which displays—incontrast to Bax—an anti-apoptotic activity) being operably linked to apromoter effective to cause transcription of the polynucleotide in thecell. It is reported that the expression of the Bax-ω-polypeptide iseffective to inhibit apoptosis in the cell. Perez et al. in Nat. Genet.1999, 21(2), 200–203 have indicated that apoptosis plays a fundamentalrole in follicular atresia and they suggest to selectively disrupt theBax function in order to extend the ovarian lifespan.

Bax down-regulation up to inhibition could indeed represent aninteresting therapy for all diseases associated with apoptosis,including neurodegenerative diseases (e.g. Alzheimer's disease,Parkinson's disease, diseases associated with polyglutamine tractsincluding Huntington's disease, spino-cerebellar ataxias anddentatorubral-pallidoluysian atrophy; amyotrophic lateral sclerosis,retinitis pigmentosa and multiple sclerosis, epilepsy), ischemia(stroke, myocardial infarction and reperfusion injury), infertility(like premature menopause, ovarian failure or follicular atresia),cardiovascular disorders (arteriosclerosis, heart failure and hearttransplantation), renal hypoxia, hepatitis and AIDS.

Hence, it is an objective of the present invention to provide compoundsenabling the treatment of apoptosis-related disorders, including notablythe above mentioned diseases.

It is specifically an objective of the present invention to provide atreatment of apoptosis related disorders by specifically regulating theBax function, e.g. by modulating, in particular by down-regulating up toinhibiting, the Bax function or by down-regulating, up to inhibiting,the Bax activation.

It is notably an objective of the present invention to provide smallmolecule pharmaceuticals, more specifically non-protein or non-peptidemolecules that avoid essentially all of the drawbacks arising from theuse of large peptides or proteins (e.g. restricted bio-availability aswell as problems arising from in vivo intolerance thereto), however,which are suitable for the treatment of a number of diseases associatedwith abnormal apoptosis. It is particularly an objective of the presentinvention to provide small molecule chemical compounds being suitableBax modulators (e.g. compounds inhibiting the Bax function or inhibitingthe Bax activation) so to be available for a convenient method oftreating diseases involving abnormal apoptosis. Moreover, it is anobjective of the present invention to provide methods for preparing saidsmall molecule chemical compounds. It is furthermore an objective of thepresent invention to provide a new category of pharmaceuticalformulations for the treatment of a host of diseases. It is finally anobjective of the present invention to provide a method of treatingdiseases that are caused by abnormal apoptosis.

DESCRIPTION OF THE INVENTION

The aforementioned objectives have been met according to the independentclaims which are set out hereinafter in the description. Preferredembodiments are set out within the dependent claims.

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds according to the invention and areintended to apply uniformly throughout the specification and claimsunless an otherwise expressly set out definition provides a broaderdefinition.

“C₁–C₆-alkyl” refers to monovalent alkyl groups having 1 to 6 carbonatoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and thelike.

“Aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to14 carbon atoms having a single ring (e.g. phenyl) or multiple condensedrings (e.g. naphthyl). Preferred aryl include phenyl, naphthyl,phenantrenyl and the like.

“C₁–C₆-alkyl aryl” refers to C₁–C₆-alkyl groups having an arylsubstituent, including benzyl, phenethyl and the like.

“Heteroaryl” refers to a monocyclic heteromatic, or a bicyclic or atricyclic fused-ring heteroaromatic group. Particular examples ofheteroaromatic groups include optionally substituted pyridyl, pyrrolyl,furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotiazolyl,isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxa-zolyl, quinolizinyl,quinazolinyl, pthalazinyl, quinoxalinyl, cinnnolinyl, napthyridinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,xanthenyl or benzoquinolyl.

“C₁–C₆-alkyl heteroaryl” refers to C₁–C₆-alkyl groups having aheteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl,2-(1H-indol-3-yl)ethyl and the like.

“Alkenyl” refers to alkenyl groups preferably having from 2 to 6 carbonatoms and having at least 1 or 2 sites of alkenyl unsaturation.Preferable alkenyl groups include ethenyl (—CH═CH₂), n-2-propenyl(allyl, —CH₂CH═CH₂) and the like.

“Alkynyl” refers to alkynyl groups preferably having from 2 to 6 carbonatoms and having at least 1–2 sites of alkynyl unsaturation, preferredalkynyl groups include ethynyl (—C≡CH), propargyl (—CH₂C≡CH), and thelike.

“Acyl” refers to the group (O)R where R includes “C₁–C₆-alkyl”, “aryl”,“heteroaryl”, “C₁–C₆-alkyl aryl” or “C₁–C₆-alkyl heteroaryl”.

“Acyloxy” refers to the group —OC(O)R where R includes “C₁–C₆-alkyl”,“aryl”, “heteroaryl”, “C₁–C₆-alkyl aryl” or “C₁–C₆-alkyl heteroaryl”.

“Alkoxy” refers to the group —O—R where R includes “C₁–C₆-alkyl” or“aryl” or “heteroaryl” or “C₁–C₆-alkyl aryl” or “C₁–C₆-alkylheteroaryl”. Preferred alkoxy groups include by way of example, methoxy,ethoxy, phenoxy and the like.

“Alkoxycarbonyl” refers to the group C(O)OR where R includes“C₁–C₆-alkyl” or “aryl” or “heteroaryl” or “C₁–C₆-alkyl aryl” or“C₁–C₆-alkyl heteroaryl”.

“Aminocarbonyl” refers to the group C(O)NRR′ where each R, R′ includesindependently hydrogen or C₁–C₆-alkyl or aryl or heteroaryl or“C₁–C₆-alkyl aryl” or “C₁–C₆-alkyl heteroaryl”.

“Acylamino” refers to the group —NR(CO)R′ where each R, R′ isindependently hydrogen or “C₁–C₆-alkyl” or “aryl” or “heteroaryl” or“C₁–C₆-alkyl aryl” or “C₁–C₆-alkyl heteroaryl”.

“Halogen” refers to fluoro, chloro, bromo and iodo atoms.

“Sulfonyl” refers to group “—SO₂—R” wherein R is selected from H,“aryl”, “heteroaryl”, “C₁–C₆-alkyl”, “C₁–C₆-alkyl” substituted withhalogens e.g. an —SO₂—CF₃ group, “C₁–C₆-alkyl aryl” or “C₁–C₆-alkylheteroaryl”.

“Sulfoxy” refers to a group “—S(O)—R” wherein R is selected from H,“C₁–C₆-alkyl”, “C₁–C₆-alkyl” substituted with halogens e.g. an —SO—CF₃group, “aryl”, “heteroaryl”, “C₁–C₆-alkyl aryl” or “C₁–C₆-alkylheteroaryl”.

“Thioalkoxy” refers to groups —S—R where R includes “C₁–C₆-alkyl” or“aryl” or “heteroaryl” or “C₁–C₆-alkyl aryl” or “C₁–C₆-alkylheteroaryl”. Preferred thioalkoxy groups include thiomethoxy,thioethoxy, and the like.

“Substituted or unsubstituted”: Unless otherwise constrained by thedefinition of the individual substituent, the above set out groups, like“alkyl”, “alkenyl”, “alkynyl”, “aryl” and “heteroaryl” etc. groups canoptionally be substituted with from 1 to 5 substituents selected fromthe group consisting of “C₁–C₆-alkyl”, “C₁–C₆-alkyl aryl”, “C₁–C₆-alkylheteroaryl”, “C₂–C₆-alkenyl”, “C₂–C₆-alkynyl”, primary, secondary ortertiary amino groups or quarter-nary ammonium moieties, “acyl”,“acyloxy”, “acylamino”, “aminocarbonyl”, “alkoxycar-bonyl”, “aryl”,“heteroaryl”, carboxyl, cyano, halogen, hydroxy, mercapto, nitro,sulfoxy, sulfonyl, alkoxy, thioalkoxy, trihalomethyl and the like.Alternatively, said substitution could also comprise situations whereneighboring substituents have undergone ring closure, notably whenviccinal functional substituents are involved, thus forming e.g.lactams, lactons, cyclic anhydrides, but also acetals, thioacetals,aminals formed by ring closure for instance in an effort to obtain aprotective group.

“Pharmaceutically acceptable salts or complexes” refers to salts orcomplexes of the below-identified compounds of formula I that retain thedesired biological activity. Examples of such salts include, but are notrestricted to acid addition salts formed with inorganic acids (e.g.hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid,pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid,naphthalene disulfonic acid, and poly-galacturonic acid. Said compoundscan also be administered as pharmaceutically acceptable quaternary saltsknown by a person skilled in the art, which specifically include thequarternary ammonium salt of the formula —NR,R′,R″⁺Z⁻, wherein R, R′, R″is independently hydrogen, alkyl, or benzyl, and Z is a counterion,including chloride, bromide, iodide, —O-alkyl, toluenesulfonate,methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate,succinate, acetate, glycolate, maleate, malate, fumarate, citrate,tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).

“Pharmaceutically active derivative” refers to ally compound that uponadministration to the recipient, is capable of providing directly orindirectly, the activity disclosed herein.

“Enantiomeric excess” (ee) refers to the products that are obtained byan essentially enantiomeric synthesis or a synthesis comprising anenantioselective step, whereby a surplus of one enantiomer in the orderof at least about 52% ee is yielded. In the absence of an enantiomericsynthesis, racemic products are usually obtained that do however alsohave the inventive set out activity as modulators of the Bax function,e.g. Bax inhibitors (antagonists).

Quite surprisingly, it was now found that the pyrrolidine derivativesaccording to formula I are suitable pharmaceutically active agents,notably by effectively modulating the Bax function or by modulating theBax activation or expression. The compounds according to formula I areparticularly interesting as they are preferably available to oraladministration and therefore provide a good bio-availability. They couldbe prescribed by a physician and require only minor supervision.

The compounds according to the present invention are those of formula I.

Said formula also comprises its geometrical isomers, its opticallyactive forms as enantiomers, diastereomers and its racemate forms, aswell as pharmaceutically acceptable salts thereof. Preferredpharmaceutically acceptable salts of the compound I, are acid additionsalts formed with pharmaceutically acceptable acids like hydrochloride,hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate,acetate, benzoate, succinate, fumarate, maleate, lactate, citrate,tartrate, gluconate, methanesulfonate, benzenesulfonate, andpara-toluenesulfonate salts.

In said formula I, X is selected from the group consisting of O, S,CR⁶R⁷, NOR⁶, NNR⁶R⁷.

A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—,—(C═O)—NH—, —(C═S)—NH, —SO₂—, —SO₂NH—, —CH₂—.

B is either an amido group of the formula —(C═O)—NR⁸R⁹ or B represents aheterocyclic residue having the formula B¹

wherein Q is NR¹⁰, O or S; n is an integer selected of 0, 1 or 2,preferably 0. m is an integer selected of 0, 1, 2 or 3, preferably 0 or1.

Y, Z and E form together with the 2 carbons to which they are attached a5–6 membered aryl or heteroaryl ring.

R¹ is selected from the group comprising or consisting of unsubstitutedor substituted C₁–C₆-alkyl, unsubstituted or substituted C₂–C₆-alkenyl,unsubstituted or substituted C₂–C₆-alkynyl, unsubstituted or substitutedaryl, unsubstituted or substituted heteroaryl, unsubstituted orsubstituted saturated or unsaturated 3–8-membered cycloalkyl, acyl,unsubstituted or substituted C₁–C₆-alkyl aryl, unsubstituted orsubstituted C₁–C₆-alkyl heteroaryl, said cycloalkyl or aryl orheteroaryl groups may be fused with 1–2 further cycloalkyl or aryl orheteroaryl group.

R², R³, R⁴ and R⁵ are independently selected from each other from thegroup consisting of hydrogen, halogen, C₁–C₆-alkyl, C₁–C₆-alkoxy,preferably they are all hydrogen.

R⁶ and R⁷ are independently selected from the group comprising orconsisting of hydrogen, unsubstituted or substituted C₁–C₆ alkyl,unsubstituted or substituted C₂–C₆ alkenyl, unsubstituted or substitutedC₂–C₆ alkynyl, unsubstituted or substituted alkoxy, unsubstituted orsubstituted thioalkoxy, halogen, cyano, nitro, acyl, alkoxycarbonyl,aminocarbonyl, unsubstituted or substituted saturated or unsaturated3–8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected ofN, O, S, unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted C₁–C₆-alkyl aryl, unsubstitutedor substituted C₁–C₆-alkyl heteroaryl.

R⁸, R⁹ and R¹⁰ are independently selected from the group comprising orconsisting of hydrogen, unsubstituted or substituted C₁–C₆ alkyl,unsubstituted or substituted C₂–C₆ alkenyl, unsubstituted or substitutedC₂–C₆ alkyl, unsubstituted or substituted saturated or unsaturated3–8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected ofN, O, S, unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl.

Alternatively, each pair R⁶, R⁷ and/or R⁸, R⁹ could form together withthe N atom to which they are attached a 3–8 membered saturated orunsaturated substituted or unsubstituted heterocyclic ring which maycontain 1–2 further heteroatoms selected from N, S and O and which isoptionally fused with an aryl, heteroaryl or 3–8 membered saturated orunsaturated cycloalkyl ring.

R¹¹ is selected from the group comprising or consisting of hydrogen,unsubstituted or substituted C₁–C₆-alkyl, unsubstituted or substitutedalkenyl, unsubstituted or substituted alkynyl, hydroxy, mercapto,alkoxy, thioalkoxy, aryl, heteroaryl, halogen, nitro, cyano, acyl,acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, sulfonyl, sulfoxy,carboxyl, primary, secondary or tertiary amino groups or quarternaryammonium moieties, unsubstituted or substituted saturated or unsaturated3–8-membered cycloalkyl.

Preferred pyrrolidine derivatives are those compounds according toformula I, wherein B is a group —(C═O)—NHR⁹, in which R⁹ is selectedfrom the group consisting of unsubstituted or substituted C₁–C₆ alkyl,unsubstituted or substituted alkenyl, unsubstituted or substitutedalkyl, unsubstituted or substituted saturated or unsaturated3–6-membered cycloalkyl which optionally contains a N atom,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted C₁–C₂-alkyl aryl, unsubstitutedor substituted C₁–C₂-alkyl heteroaryl.

Preferred heteroaryls are pyridyl, pyrrolyl, furyl, thienyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl,benzo-furyl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl,benzotriazolyl, isobenzothienyl, 2,1,3-benzothiadiazolyl,2,1,3-benzoxadiazolyl, benzodioxolyl, indolyl, isoindolyl, 3H-indolyl,benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl,quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl,napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl,pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl,5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl,pteridinyl, carbazolyl, xanthenyl, acridinyl or benzoquinolyl andwhereby said heteroaryl could be fused with a 3–8-membered cycloalkylcontaining optionally 1–3 heteroatoms selected from N, O, S.

According to a further preferred embodiment the pyrrolidine derivativesaccording to the present invention carry a residue B¹ which is a fusedheterocycle of the formula

Particularly preferred pyrrolidine derivatives are those compoundsaccording to formula I wherein X is NOR⁶, and R⁶ is selected from thegroup consisting of H, unsubstituted or substituted C₁–C₆ alkyl,unsubstituted or substituted C₂–C₆ alkenyl, unsubstituted or substitutedC₂–C₆ alkynyl, unsubstituted or substituted acyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted saturated or unsaturated 3–8-membered cycloalkyl,unsubstituted or substituted C₁–C₆-aryl aryl, unsubstituted orsubstituted C₁–C₆-alkyl heteroaryl, said cycloalkyl or aryl orheteroaryl groups may be fused with 1–2 further cycloalkyl or aryl orheteroaryl groups. Particularly preferred R⁶ is H, CH₃, unsubstituted orsubstituted CH₂-phenyl or allyl.

Under no circumstances B could be a group COOR or a group —(C═O)NR(OR),whereby R is H, alkyl or acyl. Such compounds, notably having a groupB=hydroxamic acid are described in WO 99/52868 as being potentinhibitors of metalloproteases.

Further particularly preferred pyrrolidine derivatives are thosecompounds according to formula I wherein X is CHR⁶, and R⁶ is selectedfrom the group consisting of halogen, cyano, unsubstituted orsubstituted C₃–C₆ allyl, unsubstituted or substituted C₂–C₆ alkenyl,unsubstituted or substituted C₂–C₆ alkynyl, unsubstituted or substitutedalkoxy, unsubstituted or substituted thioalkoxy, nitro, acyl,alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl, unsubstituted or substitutedsaturated or unsaturated 3–8-membered cycloalkyl, unsubstituted orsubstituted C₁–C₆-alkyl aryl, unsubstituted or substituted C₁–C₆-alkylheteroaryl, said cycloalkyl or aryl or hetero-aryl groups may be fusedwith 1–2 further cycloalkyl or aryl or heteroaryl groups. Particularlypreferred R⁶ is halogen, cyano, C₁–C₆ alkyl or an unsubstituted orsubstituted phenyl group.

Further preferred pyrrolidine derivatives are those compounds accordingto formula I, wherein X is O.

According to a further preferred embodiment the pyrrolidine derivativeshave a substituent A being —(C═O)—, or —(C═O)—NH—, or —SO₂—, mostpreferred is —(C═O)—.

More preferred groups R¹ are unsubstituted or substituted C₁–C₆-alkyl,C₂–C₆-alkenyl, unsubstituted or substituted C₂–C₆-alkynyl, aryl,heteroaryl, saturated or unsaturated 3–8-membered cycloalkyl and stillmore preferred R¹ are C₁–C₆-alkyl or aryl. A particularly preferredsubstituent R¹ is biphenyl.

According to a most preferred embodiment, the pyrrolidine derivativesaccording to for-mula I are those wherein X is NOR⁶ or ═CHCl, R⁶ is aC₁–C₆-alkyl or aryl or C₁–C₆-alkyl aryl group, B is an amido group ofthe formula —(C═O)NHR⁹), wherein R⁹ is as above defined, A is C═O and R¹is a C₁–C₆-alkyl-aryl, an aryl or a C₁–C₆-alkyl group. Even morepreferred are those pyrrolidine derivatives, wherein X is either ═CH—Cl,or ═NOR⁶, R⁶ is a methyl or phenyl group, B is an amido group of theformula —(C═O)NHR⁹), wherein R⁹ is a C₁–C₆-alkyl-aryl, an aryl, aC₁–C₆-alkyl which is substituted by a primary, secondary or tertiaryamine, A is C═O and R¹ is a diphenyl methyl or a phenyl group.

The compounds of formula I may contain one or more asymmetric centersand may therefore exist as enantiomers or diasteroisomers. It is to beunderstood that the invention includes both mixtures and separateindividual isomers or enantiomers of the compounds of formula I. In aparticularly preferred embodiment the pyrrolidine derivatives accordingto formula I are obtained in an enantiomeric excess of at least 52% ee,preferably of at least 92–98% ee. Also E/Z isomers with regard topyrrolidine derivatives having residues X being ═CR⁶R⁷ whereby both R⁶R⁷are different from each other, and/or with regard to pyrrolidinederivatives having residues X being ═NOR⁶ or ═NNR⁶R⁷ are comprised bythe present invention.

Specific examples of compounds of formula I include the following:

-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-methoxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone    O-methyloxime-   (2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-([1,1′-biphenyl]4-ylcarbonyl)-4-(methoxy-imino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-acetoacetyl-N-benzyl-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-furylmethyl)-2-pyrrolidinecarboxamide-   (2S,4E)-1-[(4-chlorophenoxy)acetyl]-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-allyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-(cyanomethylene)-N-(2-furylmethyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-acetyl-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-furylmethyl)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)car-bonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-benzyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-methyl-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-(diphenylacetyl)-4-(ethoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-4-(cyanomethylene)-1-(diphenylacetyl)-2-pyrrolidinecarboxamide-   (3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-(diphenylacetyl)-3-pyrrolidinone    O-methyloxime-   (2S)-2-[1-([1,1′-biphenyl]-4-ylcarbonyl)-4-methylene-2-pyrrolidinyl]-1H-benzimidazole-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-methoxyethyl)-2-pyrrolidinecarboxamide-   (3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-(diphenylacetyl)-3-pyrrolidinone    O-allyloxime-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(3,4-dimethoxybenzyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-acetoacetyl-4-(methoxyimino)-N-(1-naphthylmethyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-allyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(diphenylacetyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N¹-pentyl-N²-(6-quinolinyl)-1,2-pyrrolidinedicarboxamide-   (2S,4EZ)-4-(chloromethylene)-1-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide-   (2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-methylene-2-pyrrolidine-carboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-6-quinolinyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-benzylidene-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-acetoacetyl-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-acetyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N¹-(3,5-dichlorophenyl)-N²-(6-quinolinyl)-1,2-pyrrolidinedicarboxamide-   (2S,4EZ)-4-(methoxyimino)-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-(chloromethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-(diphenylacetyl)-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[2-(diethylamino)ethyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-[4-(dimethylamino)butanoyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-benzyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-(ethoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N²-Cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N¹-(3-methoxyphenyl)-1,2-pyrrolidinedicarboxamide-   (2S,4EZ)-1-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phenethyl-4-{[(4-methoxybenzyl)-oxy]imino}-2-pyrrolidinecarboxamide-   (2S)-N-(2-furylmethyl)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidine-carboxamide-   (2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-(diphenylacetyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-benzoyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quinolinyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-acetoacetyl-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}    N²-[(2RS)-2-hydroxy-2-phenethyl]-N¹-pentyl-1,2-pyrrolidinedicarboxamide-   (2S,4EZ)-4-[(benzyloxy)imino]-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide-   (2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-methylene-N-(6-quinolinyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-(diphenylacetyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-(4-Cyanobenzoyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quinolinyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(methoxyacetyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(1,3-benzodioxol-5-ylmethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (3EZ,5S)-5-[(4-acetyl-1-piperazinyl)carbonyl]-1-acryloyl-3-pyrrolidinone    O-(3,4-dichlorobenzyl)oxime-   (2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-methylene-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-(cyanomethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-3-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-(4-benzoylbenzoyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-(3-phenoxybenzoyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-(2-phenoxybenzoyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-N-methyl-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S,2S,3R,4R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(trans-4-hydroxycyclohexyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2R,S)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(]-hydroxycyclohexyl)methyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1-hydroxycyclohexyl)methyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1-hydroxycyclohexyl)methyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]4-ylcarbonyl)-N-[(2R,)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)-propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]4-ylsulfonyl)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(2-naphthyl)ethyl]4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N[(2R)-2hydroxy-2-phenylethyl]-4(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-(3-hydroxypropyl)-4-(methoxyimino)-2pyrrolidinecarboxamide-   (3EZ,5S)-1-([1,1′-biphenyl]4-ylcarbonyl)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-1-[4-(4-pyridinyl)benzoyl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-1-[4(3-pyridinyl)benzoyl]-3pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]3-pyrrolidinone    O-methyloxime-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-benzyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-benzyl-N-(2-hydroxyethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbony}-1-[4-(4-pyridinyl)benzoyl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-1-[4-(3-pyridinyl)benzoyl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylsulfonyl)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-3-pyrrolidinone    O-methyloxime-   (2S,4EZ)-1-([1,1′-biphenyl]4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-anilinoethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-anilinoethyl)-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-3-pyrrolidinone    O-methyloxime-   (2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(3-amino-3-oxopropyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(4-hydroxybutyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-(4-hydroxybutyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1R,2R)-2-hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1R,2S,3R,4S)-3-(hydroxymethyl)bicyclo-[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1R,2S)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4E and    4Z)-N-[(2RS)-2-hydroxy-2-phenylethyl]4-(methoxyimino)-1-[(2′-methyl[1,1-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4E and    4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4E and    4Z)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1R,2S)-2-(hydroxymethyl)cyclohexyl-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2RS)-3-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-carbonyl}amino)-2-hydroxypropanoic    acid-   (2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1RS)-2-hydroxy-1-methylethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   4-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-amino)butanoic    acid-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(2-naphthyl)ethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1RS)-2-hydroxy-1-methylethyl]4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4    (methoxyimino)-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (3EZ,5S)-5-[(4-hydroxy-1-piperidinyl)carbonyl)-1-[(2′-methyl[1,1′-biphenyl]4-yl)carbonyl]-3-pyrrolidinone    O-methyloxime-   (2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(3-hydroxypropyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-amino-2-oxoethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-amino-2-oxoethyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2R,3S,4R)-3-(hydroxymethyl)-bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1R,2S,3R,4S)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(trans-4hydroxycyclohexyl)    1-[(2′-methoxy[1,1′-biphenyl]-4yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′-methyl    1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2R-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]1-[(2′-methyl[1,1′-biphenyl]4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2R,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2R,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′-cyano[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,6′-dimethyl]1,1′-biphenyl]-4-yl)carbonyl]-4-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′-cyano[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(3′,4′-dichloro[1,1-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,6′-dimethyl    1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-amino-2-oxoethyl)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-amino-2-oxoethyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4    (methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,3-dimethyl[1,1-biphenyl]-4-yl)carbonyl]-1N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′-cyano[1,1′-biphenyl]-4-yl)carbonyl]-N-[(1R,2R)-2-hydroxymethyl)-cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (3EZ,5S)-5-(3,4-dihydro-2(1H)-isoquinolinylcarbonyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-3-pyrrolidinone    O-methyloxime-   (2S,4EZ)-N-[(1R)-2-hydroxy-1-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,6′-dimethyl    [1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(1R,2S)-2-hydroxy-1,2-diphenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2RS)-2-[({(2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-pyrrolidinyl}carbonyl)amino]-3-phenylpropanoic    acid-   (2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4(methoxyimino)-2-pyrrolidinecarboxamide-   4′-{[(2S,4EZ)-2-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl})-4-(methoxyimino)-pyrrolidinyl]carbonyl}[1,1′-biphenyl]-2–carbonitrile-   (3EZ,5S)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-({4-[4-(trifluoromethyl)phenyl]-1-piperazinyl}carbonyl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}carbonyl)-3-pyrrolidinone    O-methyloxime-   (2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-(methoxyimino)-N-methyl-1-[(2′-methyl[1,1′-biphenyl]4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-4(methoxyimino)-N,N-dimethyl-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(3S)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(3S)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2′-(trifluoro-methyl)[1,1′-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2′-chloro[1,1′-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-hydroxyphenyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[2-(hydroxymethyl)phenyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4E and    4Z)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-4methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-phenylethyl)-2-pyrrolidinecarboxamide-   (2S)-1-(diphenylacetyl)-N-(1-naphthylmethyl)-4-oxo-2-pyrrolidinecarboxamide-   (2S)-N1-(3,5-dichlorophenyl)-N2-(3,4-dimethoxybenzyl)-4-oxo-1,2-pyrrolidinedicarboxamide-   (2S)-4-oxo-1-(phenoxyacetyl)-N-[2-(1H-pyrrol-1-yl)phenyl]-2-pyrrolidinecarboxamide

Thereby, the most preferred compounds are those which are selected fromthe group consisting of:

-   (4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino)ethyl]-4-{[(4-methoxybenzyl)-oxy]imino}-2-pyrrolidinecarboxamide-   (4EZ)-N²-(2-hydroxyethyl)-4-(methoxyimino)-N¹-pentyl-1,2-pyrrolidinedicarboxamide-   (4EZ)-4-benzylidene-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino)ethyl]-2-pyrrolidinecarboxamide-   (4EZ)-4-[(alkyloxy)imino]-1-(4–cyanobenzoyl)-N-[2-(1H-pyrrol-1-yl)phenyl]-2-pyrrolidinecarboxamide-   (4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(2-furylmethyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide-   (4EZ)-4-(methoxyimino)-N¹-(3-methoxyphenyl)-N²-(2-thienylmethyl)-1,2-pyrrolidinedicarboxamide-   (4EZ)-2-{[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]carbonyl}-4-(methoxyimino)-N-pentyl-1-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-1-nonanoyl-2-pyrrolidinecarboxamide

A further aspect of the present invention is related to the use of thepyrrolidine derivatives according to formula I for the preparation ofpharmaceutical compositions for the treatment of diseases includingAlzheimer's disease, Parkinson's disease, diseases associated withpolyglutamine tracts including Huntington's disease, spinocerebellarataxias and dentatorubral-pallidoluysian atrophy; amyotrophic lateralsclerosis, Crohn's disease, retinitis pigmentosa and multiple sclerosis,epilepsy), ischemia (stroke, myocardial infarction and reperfusioninjury), infertility (like premature menopause, ovarian failure orfollicular atresia), cardiovascular disorders (arteriosclerosis, heartfailure and heart transplantation), renal hypoxia, hepatitis and AIDS.

According to a preferred embodiment, the above cited diseases or diseasestates are treated by the modulation of the Bax function, or themodulation (e.g. the inhibition) of the activation or expression of Bax,respectively, via the use of compounds of formula I, whereby the termBax function notably comprises the actually active form of Bax as anoligomer (see B. Antonsson et al. in Biochem. J., Vol. 345, 2000, pages271–278). Through the modulation of the Bax function, a convenientmethod of treatment of disorders mediated by Bax is expected, includingin particular neuronal disorders and/or disorders of the immune system.Said modulation could notably involve the inhibition of the activity(activation) and/or of the expression of Bax. Also, said modulation ofthe Bax function or activity could actually comprise the inhibition ordisruption for instance of the Bid interaction with Bax, which has beenshown to play a role within the context of the Bax activation leading tocytochrome c release (see J. C. Martinou et al. in The Journal of CellBiology, Vol. 144, No. 5, Mar. 8, 1999, pages 891–901). As a result ofthe inhibition of the Bax activation by Bid upon using the compoundsaccording to formula I, the cytochrome c release could be inhibited oressentially blocked, thus providing a convenient means to modulate theabove described apoptosis pathways. As a result, by said modulation ofthe apoptosis pathways a whole variety of disorders associated withabnormal apoptosis is expected to be treated.

It is reported herein that the compounds of formula I are suitable to beused as a medicament, i.e. they are suitable for use in treatingdiseases, like disorders of the autoimmune system and neuronal system ofmammals, notably of human beings. More specifically, the compoundsaccording to formula I, alone or in the form of a pharmaceuticalcomposition, are useful for the modulation, in particular for theinhibition, of the Bax function and/or the Bax activation. Morespecifically, the compounds according to formula I, alone or in the formof a pharmaceutical composition, are useful for the treatment orprevention of disorders associated with abnormal expression oractivation of Bax. The compounds according to formula I could beemployed alone or in combination with further pharmaceutical agents. Thecompounds of formula I are suitable to be used as a medicament alone orin the form of a pharmaceutical composition together with suitablecarriers, diluents or excipients. The compounds of formula I aresuitable to be used for the preparation of orally administratedpharmaceutical compositions.

Thus, according to the present invention, compounds pursuant to formulaI are particularly useful for the treatment or prevention of immuno-and/or neuronal-related diseases or pathological states in whichpreferably the modulation, in particular the inhibition, of the Baxfunction and/or the Bax activation plays a crucial role, such asneurodegenerative diseases (e.g. Alzheimer's disease, Parkinson'sdisease, diseases associated with polyglutamine tracts includingHuntington's disease, spinocerebellar ataxias anddentatorubral-pallidoluysian atrophy; amyotrophic lateral sclerosis,Crohn's disease, retinitis pigmentosa and multiple sclerosis, epilepsy),ischemia (stroke, myocardial infarction and reperfusion injury),infertility (like premature menopause, ovarian failure or follicularatresia), cardiovascular disorders (arteriosclerosis, heart failure andheart transplantation), renal hypoxia, hepatitis and AIDS.

Still a further aspect of the present invention is related to theactually novel pyrrolidine compounds of formula I. Some very fewcompounds have actually been disclosed prior to the filing of thepresent application, without any medical use though. Said knowncompounds of formula I are those, wherein

-   X is (═CH₂), A is —(C═O)—O—, R¹ is a t-butyl group and B is    —(C═O)—NMe₂ (Tetrahedron 53(2), 539, 1997); —(C═O)—NHMe (WO    95/47718); —(C═O)—NH—CH(Me)—(C═O)—NH—CH(Me)—COOH (WO 95/47718); or    —(C═O)—NH—CH(COOCH₂-Ph)—CH₂—COOPh (Tetrahedron 48(31), 6529, 1992).-   X is (═CHR⁶) with R⁶ being cyclohexylmethyl, A is —(C═O)—O—, R¹ is a    t-butyl group and is —(C═O)—NH-t-butyl (Biorg. Chem. Lett. 3(8),    1485, 1993).-   X is C₁–C₂₀ alkylidene, A is —(C═O)—O—, R¹ is a t-butyl and B is    wherein R is C₁–C₁₂ alkyl and Hal is Cl, Br, J. Said compounds are    disclosed in DE-1,932,823 as intermediates.-   X is C₁–C₂₀ alkylidene, A-R¹ is a protective group and B is    with R being H or C₁–C₁₂ alkyl (GB-1,118,306)

Also excluded are the following compounds:

which is disclosed in WO 00/08015 as being an FSH agonist.

which is disclosed in Bioorg Med. Chem. (1996), 4(8), pp.1365–77 asbeing useful for the treatment of infections.

wherein: Pin is—NH—CH[C₆H₃(OMe)₂]C₆H₄OCHCO-Gly-NH(CH₂)₆NH-MA/DMA-polyethylene pin(Tetrahedron Letters, Vol. 36 (1995) No.28, pp.5081–5084). No biologicalactivity is disclosed for said molecule.

The above two compounds are disclosed in J. Med. Chem, 29 (1986)pp.959–971 for their ability to reverse electroconvulsive shock-inducedamnesia in rodents.

Int. J. Pept. Protein Res. (1982), 20(5), pp.438–42.). No biologicalactivity is disclosed for said molecule.

Hence, the novel compounds are those of the formula I, wherein the abovementioned known compounds are excluded.

Still a further object of the present invention is a process forpreparing the pyrrolidine derivatives according to formula I.

The pyrrolidine derivatives exemplified in this invention can beprepared from readily available starting materials using the followinggeneral methods and procedures. It will be appreciated that wheretypical or preferred experimental conditions (i.e. reactiontemperatures, time, moles of reagents, solvents, etc.) are given, otherexperimental conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the parti-cular reactants orsolvents used, but such conditions can be determined by one skilled inthe art by routine optimisation procedures. Generally, the pyrrolidinederivatives according to the general formula I could be obtained byseveral processes, using both solution-phase and solid-phase chemistryprotocols. Depending on the nature of A, B, and X, certain processeswill, in some instances, be preferred over others, and it is assumedthat the choice of the most suitable process will be obvious to thepractitioner skilled in the art.

According to one process, pyrrolidine derivatives according to thegeneral formula I, whereby the substituent B is C(O)—NR⁸R⁹, with R⁸ andR⁹ being defined as above, are prepared from the corresponding suitablyN-protected 4-substituted pyrrolidine derivatives II, whereby thesubstituent X is as above defined, by solution-phase chemistry protocolssuch as described in the Examples and shown in Scheme I, below. Thesuitably N-protected 4-substituted pyrrolidine derivatives II are firstreacted with primary or secondary amines III, whereby the substituentsR⁸ and R⁹ are as above defined, using conditions and methods well knownto those skilled in the art to prepare an amide from an amine and acarboxylic acid or a carboxylic acid derivative, using standard peptidecoupling agents, such as e.g. DIC, EDC, TBTU, DECP, or others, to yieldcompounds of formula IV. Removal of the N-protecting group using theappropriate deprotection agents produces deriva-tives of formula V.These can be treated with acylating agents of general formula VI,whereby the substituent R¹ is as above defined, while LG could be anyappropriate leaving group. Preferred acylating agents VI are acidchlorides (VIa), used in conjunction with a tertiary amine base, orcarboxylic acids (VIb), used in conjunction with a peptide couplingagent, e.g. from the above mentioned group, to yield the products ofgeneral formula I, with B being defined as C(O)N⁸R⁹ (Ia).

Other derivatives of formula I are prepared using known modifications tothe Scheme 1 reaction sequence. Compounds of formula I wherein A isdifferent from the carbonyl functionality are prepared by replacingformula VI compounds with compounds containing the appropriatefunctional groups, e.g. sulfonyl chlorides, isocyanates,isothiocyanates, chloroformates, substituted alkyl halides, or others toyield sulfonamide, urea, thiourea, carbamate, substituted alkylderivatives, or others, respectively.

Compounds of formula II, whereby the substituent X is CR⁶R⁷, and R⁶ andR⁷ are as above defined, can be prepared from compounds of generalformula VII by Wittig-type reactions with anions of phosphoranes such asVIIIa and/or of phosphonates such as VIIIb, followed by saponificationof the ester function using standard synthetic techniques, ashereinafter described in the Examples and shown in Scheme 2.

Compounds of general formula VII can be prepared from commerciallyavailable, suitably N-protected 4-hydroxyproline X, by a reactionsequence consisting of oxidation and esterification, using standardsynthetic techniques as hereinafter described in the Examples and shownin Scheme 3.

Compounds of formula II, wherein the substituent X is NOR⁶ or NNR⁶R⁷,and R⁶ and R⁷ are as above defined, can be prepared from compounds ofgeneral formula XI by reaction with substituted hydroxylamines XIIaand/or substituted hydrazines and/or hydrazides XIIb using standardsynthetic techniques as hereinafter described in the Examples and shownin Scheme 4.

Compounds of formula XIIa are commercially available or prepared bystandard synthetic techniques as hereinafter described in the Examples.Compounds of formula II with X=S are accessible from the correspondingsuitably protected ketopyrrolidine intermediates VII through standardfunctional group interconversion methods well known to the personskilled in the art, such as, e.g., by treatment with Lawesson's reagentor others (Pedersen, B. S. et al.; Bull. Soc. Chim. Belg. 1978, 87,223),followed by saponification.

According to another process, pyrrolidine derivatives according to thegeneral formula I, whereby the substituent B is a heterocyclic residueB1 as above defined, and the substituents are as above defined, areprepared from the corresponding suitably N-protected 4-substitutedpyrrolidine derivatives II, whereby the substituent X is as abovedefined, by solution-phase chemistry protocols such as described in theExamples and shown in Scheme 5, below. The starting suitably N-protected4-substituted pyrrolidine derivatives II are first reacted withortho-substituted primary anilines of general formula XIII, whereby thesubstituents Q, Z, E, Y, and R¹¹ are as above defined, using standardpeptide coupling agents, such as DIC, EDC, THTU, DECP, or others,followed by exposure to dilute weak acid, such as acetic acid, in asuitable organic solvent, such as DCM, to promote cyclisation yieldingcompounds of formula XIV. Removal of the N-protecting group using theappropriate deprotection agents produces cyclic derivatives of formulaXV. These can be treated with acylating agents of general formula VI,whereby the substituent R¹ is as above defined, while LG could be anyappropriate leaving group. Preferred acylating agents VI are acidchlorides (VIa), used in conjunction with a tertiary amine base, orcarboxylic acids (VIb), used in conjunction with a peptide couplingagent, e.g. from the abovementioned group, to yield the products ofgeneral formula I, with B being defined as B1 (Ib).

Other derivatives of formula I are prepared using known modifications tothe Scheme 5 reaction sequence. Compounds of formula I wherein A isdifferent from the carbonyl functionality are prepared by replacingformula VI with compounds containing the appropriate functional groups,e.g. sulfonyl chlorides, isocyanates, isothiocyanates, chloroformates,substituted alkyl halides, or others to yield sulfonamide, urea,thiourea, carbamate, substituted alkyl derivatives, or others,respectively.

According to another general process, summarized in Scheme 6,pyrrolidine derivatives according to the general formula I, whereby thesubstituents A, B, X, and R¹ are as above defined, are prepared fromcompounds of formula XVI, using the synthetic techniques as outlined inSchemes 2 and 4. As further shown in Scheme 6, compounds of formula XVIare accessible either from XI, following, e.g., the syntheticmethodologies introduced in Schemes 1 and 5, or from Ic throughhydrolysis of the methyloxime moiety, e.g. under mild hydrolysisconditions as described hereinafter in the Examples. This presentsynthetic strategy is most preferred when X is NOH or NNR⁶R⁷, wherebythe substituents R⁶ and R⁷ are as above defined.

According to yet another process, pyrrolidine derivatives according tothe general formula I, whereby the substituents A, B, X, and R¹ are asabove defined, are prepared from the corresponding suitably N-protected4-substituted pyrrolidine derivatives II, whereby the substituent X isabove defined, by a solid-phase protocol such as described in theexamples and shown in Scheme 7, below. The N-Boc-protected 4-substitutedpyrrolidine derivative II is reacted e.g. with Kaiser oxime resin usingstandard carbodiimide-mediated coupling conditions well known to thepractitioner skilled in the art, followed by Boc-deprotection withdilute TFA in DCM, or with BF₃.OEt₂ in dilute HOAc in DCM, to givecompound XIX. The latter compound can be treated with acylating agentsof general formula VI, whereby the substituent R¹ is as above defined,while LG could be any appropriate leaving group. Preferred acylatingagents VI are acid chlorides (VIa), used in conjunction with a tertiaryamine base, or carboxylic acids (VIb), used in conjunction with apeptide coupling agent, e.g. DIC or EDC, to yield products of generalformula XX.

Compounds of formula I wherein A is different from the carbonylfunctionality are pre-pared by replacing formula VI with compoundscontaining the appropriate functional groups, e.g. sulfonyl chlorides,isocyanates, isothiocyanates, chloroformates, substituted allyl halides,or others to yield sulfonamide, urea, thiourea, carbamate, substitutedalkyl derivatives, or others respectively.

In order to obtain the final compounds of general formula I, the linkageto the resin is cleaved by prolonged treatment with amines of generalformulae III or XIII and low percentages of a weak acid, such as HOAc.The cycles within the below Scheme 7 illustrate the resign beads towhich the corresponding compounds are linked during the solid phasesynthesis. Other derivatives of formula I are prepared using knownmodifications to, or variations of, the Scheme 7 reaction sequence.Further to the above mentioned Kaiser oxime resin, other suitablereagents, notably resins, known to a person skilled in the art, could beemployed for the solid-phase synthesis of compounds of general formulaI.

The reaction sequences outlined in the above Schemes providesenantiomerically pure compounds of formula I, if enantiomerically purestarting materials are used (R) as well as (S) enantiomers can beobtained depending upon whether (R) or (S) forms of commerciallyavailable compounds of formulas II, III, VI, and/or X were used as thestarting materials.

However, the reaction sequences outlined in the above Schemes usuallyprovides mixtures of (E) and (Z) isomers with respect to thesubstituents on the exocyclic double bond of the pyrrolidine ring. Inall cases studied, these (E)/(Z)-isomers could be separated by standardchromatography techniques well known to the person skilled in the art,such as by reversed phase high-pressure liquid chromatography (HPLC) orsilica gel flash chromatography (FC). The assignment of the absoluteconfiguration of the exocyclic double bond was performed usingNMR-techniques well described in the literature as will be known to thepractitioner skilled in the art (for configurationnal assignements ofe.g. oxime functionalities, see e.g. E. Breitmaier, W. Voelter Carbon-13NMR Spectroscopy, 3rd Ed, VCH, 1987, p. 240).

According to a flirter general process, compounds of formula I can beconverted to alternative compounds of formula I, employing suitableinterconversion techniques such as hereinafter described in theExamples.

If the above set out general synthetic methods are not applicable forobtaining compounds according to formula I and/or necessaryintermediates for the synthesis of compounds of formula I, suitablemethods of preparation known by a person skilled on the art should beused. In general, the synthesis pathways for any individual compound offormula I will depend on the specific substitutents of each molecule andupon the ready availability of intermediates necessary; again suchfactors being appreciated by those of ordinary skill in the art. For allthe protection, de-protection methods, see Philip J. Kocienski, in“Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and,Theodora W. Greene and Peter G. M. Wuts in “Protective Groups in OrganicSynthesis”, Wiley-Interscience, 1991.

Compounds of this invention can be isolated in association with solventmolecules by crystallization from evaporation of an appropriate solvent.The pharmaceutically acceptable acid addition salts of the compounds offormula I, which contain a basic center, may be prepared in aconventional manner. For example, a solution of the free base may betreated with a suitable acid, either neat or in a suitable solution, andthe resulting salt isolated either by filtration or by evaporation undervacuum of the reaction solvent. Pharmaceutically acceptable baseaddition salts may be obtained in an analogous manner by treating asolution of compound of formula I with a suitable base. Both types ofsalt may be formed or interconverted using ion-exchange resintechniques.

If the above set out general synthetic methods are not applicable forthe obtention of compounds of formula I, suitable methods of preparationknown by a person skilled in the art should be used.

A final aspect of the present invention is related to the formulationscontaining the active compounds according to formula I. When employed aspharmaceuticals, the pyrrolidine derivatives of the present inventionare typically administered in the form of a pharmaceutical composition.Hence, pharmaceutical compositions comprising a compound of formula Iand a pharmaceutically acceptable carrier, diluent or excipienttherefore are also within the scope of the present invention. A personskilled in the art is aware of a whole variety of such carrier, diluentor excipient compounds suitable to formulate a pharma-ceuticalcomposition. Also, the present invention provides compounds for use as amedi-cament. In particular, the invention provides the compounds offormula I for use as Bax antagonist, for the treatment of disorders ofmammals, notably of human beings associated with inappropriate celldeath, including neurodegenerative disorders, diseases associated withpolyglutamine tracts, epilepsy, ischemia, infertility, cardiovasculardisorders, renal hypoxia, hepatitis and AIDS, either alone or incombination with other medicaments, notably in combination with furtherBax inhibitors.

The compounds of the invention, together with a conventionally employedadjuvant, carrier, diluent or excipient may be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, or in the form of sterileinjectable solutions for parenteral administration (includingsubcutaneous use). Such pharmaceutical compositions and unit dosageforms thereof may comprise ingredients in conventional proportions, withor without additional active compounds or principles, and such unitdosage forms may contain any suitable effective amount of the activeingredient commensurate with the intended daily dosage range to beemployed.

When employed as pharmaceuticals, the pyrrolidine derivatives of thisinvention are typically administered in the form of a pharmaceuticalcomposition. Such compositions can be prepared in a manner well known inthe pharmaceutical art and comprise at least one active compound.Generally, the compounds of this invention are administered in apharmaceutically effective amount. The amount of the compound actuallyadministered will typically be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the actual compound administered,the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the like.

The pharmaceutical compositions of these inventions can be administeredby a variety of routes including oral, rectal, transdermal,subcutaneous, intravenous, intramuscular, and intranasal. Depending onthe intended route of delivery, the compounds are preferably formulatedas either injectable or oral compositions. The compositions for oraladministration can take the form of bulk liquid solutions orsuspensions, or bulk powders. More commonly, however, the compositionsare presented in unit dosage forms to facilitate accurate dosing. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient. Typical unit dosage forms include prefilled,premeasured ampoules or syringes of the liquid compositions or pills,tablets, capsules or the like in the case of solid compositions. In suchcompositions, the pyrrolidine compound is usually a minor component(from about 0.1 to about 50% by weight or preferably from about 1 toabout 40% by weight) with the remainder being various vehicles orcarriers and processing aids helpful for forming the desired dosingform.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatine; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As above mentioned, the pyrrolidine compounds of formula Iin such compositions is/are typically a minor component, frequentlyranging between 0.05 to 10% by weight with the remainder being theinjectable carrier and the like.

The above described components for orally administered or injectablecompositions are merely representative. Further materials as well asprocessing techniques and the like are set out in Part 8 of Remington'sPharmaceutical Sciences, 17^(th) Edition, 1985, Marck PublishingCompany, Easton, Pa., which is incorporated herein be reference.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can also befound in the incorporated materials in Remington's Pharma-ceuticalSciences.

In the following the present invention shall be illustrated by means ofsome examples which are not construed to be viewed as limiting the scopeof the invention. The HPLC, NMR and MS data provided in the examplesdescribed below were obtained as followed. The following abbreviationsare hereinafter used in the accompanying examples: min (minute), hr(hour), g (gram), mmol (millimole), m.p. (melting point), eq(equivalents), mL (milliliter), μL (microliters), mL (milliliters), ACN(Acetonitrile), CDCl₃ (deuterated chloroform), cHex (Cyclohexanes), DCM(Dichloromethane), DECP (Diethylcyanophosphonate), DIC (Diisopropylcarbodiimide), DMAP (4 Dimethylaminopyridine) DMF (Dimethylformamide),DMSO (Dimethylsulfoxide), DMSO-d₆ (deuterated dimethylsulfoxide), EDC(1-(3-Dimethylamino-propyl)-3-ethylcarbodiimide), EtOAc (Ethyl acetate),Et₂O (Diethyl ether), HOBt (1-Hydroxybenzotriazole), K₂CO₃ (potassiumcarbonate), NaH (Sodium hydride), NaHCO₃ (Sodium bicarbonate), nBuLi (nButyllithium), TBTU(O-Benzotriazolyl-N,N,N′,N′-tetramethyluronium-tetrafluoroborate), TEA(Triethyl amine), TFA (Trifluoro-acetic acid), THF (Tetrahydrofuran),MgSO₄ (Magnesium sulfate), PetEther (Petroleum ether), rt (roomtemperature).

EXAMPLES

Intermediate 1:(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid

Commercial(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid(30 g, 0.13 mol) was dissolved in acetone (1500 ml). A mechanicalstirrer was placed in the flask and the solution stirred vigorously. Afreshly made solution of 8N chromic acid was prepared by dissolvingchromium trioxide (66.7 g, 0.667 mol) in water (40 ml), addingconcentrated sulphuric acid (53.3 ml) and adding enough water to bringthe solution volume to 115 ml. The 8N chromic acid solution (115 ml) wasthen added dropwise over a period of 30 minutes with continued vigorousstirring, the reaction's exotherm being maintained at the optimaltemperature of 25° C. by the use of an ice bath. After the completeaddition of the chromic acid, the reac-tion mixture was stirred for afurther 15 minutes—maintaining the optimal temperature of 25° C. Thereaction mixture was then quenched by the addition of methanol (20 ml).Exotherm controlled by the use of an ice bath and, if necessary, directaddition of a small amount of crushed ice to the reaction mixtureitself. The reaction mixture was filtered through a Celite pad and thenconcentrated in vacuo. The resulting acidic solution was then extractedwith ethyl acetate (3×300 ml) and the combined organic layers washedwith brine (2×100 ml). Organics then dried with magnesium sulfate andconcentrated in vacuo. Crude product recrystallised from ethyl acetateto give the white crystalline product,(2S)-1-(tertbutoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (22.55 g,76%). The antipodal intermediate,(2R)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid, wasmade according to the same protocol, starting from commercial(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid.

1H NMR (360 MHz, CDCl3); 1.4 (m, 9H), 2.5–3.0 (m, 2H), 3.7–3.9 (m, 2H),4.75 (dd, 1H)

Intermediate 2: 1-tert-butyl 2-methyl(2S)-4-oxo-1,2-pyrrolidinedicarboxylate

A solution of (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylicacid (1 g, 4.3 mmol) in a 1:1 mixture of methanol and toluene (60 ml)was made. Trimethylsilyl diazomethane (6.5 ml of a 2M solution inhexanes, 13 mmol) was then added dropwise to the stirred solution atroom temperature under nitrogen. After completion of the evolution ofnitrogen gas, the resulting yellow solution was evaporated in vacuo, andthe residue filtered through a pad of silica gel, eluting with ethylacetate. Removal of solvent from the filtrate gave a yellow oil (1.05 g,near quantitative yield).

¹H NMR (400 MHz, CDCl₃); 1.4 (m, 9H), 2.5 (m, 1H), 2.8–2.9 (m, 1H) 3.7(s, 3H), 3.9 (m, 2H), 4.6–4.8 (m, 1H).

Intermediate 3: 1-tert-butyl 2-methyl(2S,4EZ)-4-(chloromethylene)-1,2-pyrrolidinedicarboxylate

Chloromethyltriphenylphosphonium iodide (270 mg, 0.62 mmol) was added toa solution of potassium tert-butoxide (67 mg, 0.59 mmol) in anhydrousdiethyl ether (5 ml) under nitrogen and the resulting bright yellowmixture stirred for 30 minutes at ambient temperature. The reaction wasthen cooled to 0° C. and a solution of 1-tert-butyl 2-methyl(2S)-4-oxo-1,2-pyrrolidinedicarboxylate (100 mg, 0.41 mmol in 2 mlanhydrous diethyl ether) was added dropwise. The reaction was thenwarmed to room temperature and stirred for 30 minutes before addingsaturated aqueous ammonium chloride solution (0.5 ml). The organic layerwas removed in vacuo, and the aqueous washed with diethyl ether (3×5ml). The combined organic layers were dried with brine and magnesiumsulfate before filtering and removal of solvent. The desired product wasisolated by silica gel chromatography, eluting with 15% ethyl acetate inhexanes to give 105 mg (93% yield) as a off-white wax.

¹H NMR (400 MHz, CDCl₃); 1.4 (9H, m), 2.6–2.75 (m, 1H), 2.8–3.0 (m, 1H),3.65 (s, 3H), 4.1 (m, 2H), 4.4–4.5 (m, 1H) 5.9–6.0 (m, 1H).

Intermediate 4: 1-tert-butyl 2-methyl(2S)-4methylene-1,2-pyrrolidinedicarboxylate

Methyltriphenylphosphonium bromide (22 g, 61.6 mmol) was added to asolution of potas-sium tert-butoxide (6.5 g, 57.6 mmol) in anhydrousdiethyl ether (450 ml) at 0° C. under nitrogen and the resulting brightyellow mixture stirred for 30 minutes. A solution of 1-tert-butyl2-methyl (2S)-4-oxo-1,2-pyrrolidinedicarboxylate (10 g, 41.1 mmol in 150ml anhydrous diethyl ether) was added slowly to the reaction mixture,which was then warmed at 35° C. for 3 h. Saturated aqueous ammoniumchloride solution (0.5 ml) was then added. The organic layer wasremoved, and the aqueous washed with diethyl ether (3×5 ml). Thecombined organic layers were dried with brine and magnesium sulfatebefore filtering and removal of solvent. Silica gel chromatography,eluting with 15% ethyl acetate in hexanes gave the desired pro-duct 6.9g (70% yield) as a off-white wax.

¹H NMR (400 MHz, CDCl₃); 1.4 (9H, m), 2.5 (m, 1H), 2.8 (m, 1H), 3.65 (s,3H), 4.0 (m, 2H), 4.3–4.5 (m, 1H), 4.9 (m, 2H).

Intermediate 5: 1-tert-butyl 2-methyl(2S,4EZ)-4-(cyanomethylene)-1,2-pyrrolidinedicarboxylate

Diethyl cyanomethyl phosphonate (0.86 ml, 4.4 mmol) was dissolved in dryTHF (50 ml) and the solution cooled to 0° C. Sodium hydride (205 mg of a60% suspension in parrafin oil, 5.1 mmol) was then added cautiously andthe reaction stirred for 30 min. The reaction mixture was then cooled to−78° C. and a solution of 1-tert-butyl 2-methyl(2S)-4oxo-1,2-pyrrolidinedicarboxylate (1.0 g, 4.1 mmol) in dry THF (5ml) was added dropwise. The reaction was then allowed to reach roomtemperature. Saturated aqueous ammonium chloride solution (15 ml) wasthen added, followed by ethyl acetate (100 ml). (The organic layer wasremoved, and the aqueous washed with ethyl acetate (3×5 ml). Thecombined organic layers were dried with brine and magnesium sulfatebefore filtering and removal of solvent. Silica gel chromatography,eluting with 35% ethyl acetate in hexanes gave the desired compound (860mg, 80%) as an off-white wax.

¹H NMR (360 MHz, CDCl₃); 1.4 (m, 9H), 2.7–3.0 (m, 1H), 3.1–3.3 (m, 1H),3.7 (m, 3H), 4.2–4.4 (m, 2H), 4.5–4.7 (m, 1H), 5.4 (m, 1H).

Intermediate 6: 1-tert-butyl 2-methyl(2S,4EZ)-4-benzylidene-1,2-pyrrolidinedicarboxylate

Potassium tert-butoxide (6.1 g, 54 mmol) was added portionwise to asolution of benzyltriphenylphosphonium chloride (22.45 g, 58 mmol) inanhydrous dichloromethane (400 ml) and the reaction stirred at ambienttemperature for 1 h. The solution was then cooled to 0° C. and asolution of 1-tert-butyl 2-methyl(2S)-4-oxo-1,2-pyrrolidinedicarboxylate (9.36 g, 38.5 mmol) in drydichloromethane (30 ml) was added dropwise. After stirring for a further1 h at 0° C. the reaction was stirred for a further 3 h at ambienttemperature. Saturated aqueous ammonium chloride solution (30 ml) wasthen added. The organic layer was removed, and the aqueous washed withdichloromethane (3×20 ml). The combined organic layers were dried withbrine and magnesium sulfate before filtering and removal of solvent.Silica gel chromato-graphy, eluting with 30% ether in hexanes gave thedesired product 8.65 g (71% yield) as a pale yellow wax.

¹H NMR (400 MHz, CDCl₃);1.5 (m, 9H), 2.8–3.0 (m, 1H), 3.2 (m, 1H), 3.7(m, 3H), 4.2–4.4 (m, 2H), 4.5–4.6 (m, 1H), 6.3–6.4 (m, 1H), 7.1–7.5 (m,5H).

Intermediate 7:(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid

A solution was made containing(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g,21 mmol) and O-methylhydroxylamine hydrochloride (2.7 g, 32.8 mmol) inchloroform (100 ml) containing triethyl-amine (5.5 g, 55 mmol). Thereaction mixture was then stirred at ambient temperature over-night,prior to removal of solvent. The resultant crude reaction mixture wasdissolved in ethyl acetate (150 ml) and washed rapidly with 1N HCl (40ml). The acidic layer was then extracted with ethyl acetate (3×20 ml)and the combined organic layers washed with brine before drying overmagnesiom sulfate, filtering and removal of solvent in vacuo. Thedesired product (5.3 g, 94%) was isolated as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃); 1.45 (m, 91), 2.8–3.2 (m, 2H), 3.9 (s, 3H), 4.2(m, 2H), 4.5–4.7 (m, 1H).

Intermediate 8:(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid

A solution was made containing(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g,22mmol) and O-ethylhydroxylamine hydrochloride (6.4 g, 65.5 mmol) in a1:1 mixture of pyridine and ethanol (100 ml). The reaction was heated toreflux for 2.5 h before cooling and removal of solvent. The residue wasdissolved in ethyl acetate and washed rapidly with 1.3N HCl (40 ml). Theacidic layer was then extracted with ethyl acetate (3×20 ml) and thecombined organic layers washed with brine before drying over magnesiomsulfate, filtering and removal of solvent in vacuo. The desired product(5.5 g, 93%) was isolated as a pale yellow oil.

¹H NMR (400 MHz, DMSO); 1.3 (t, 3H), 1.55 (m, 9H), 2.9–2.7 (m, 1H),3.4–3.1 (m, 1H), 4.1–4.3 (m, 4H), 4.6 (m, 1H), 12–13.5 (br, 1H).

Intermediate 9:(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid

A solution was made containing(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g,22 mmol) and O-allylhydroxylamine hydrochloride monohydrate (7.2 g, 65.5mmol) in a 1:1 mixture of pyridine and ethanol (100 ml). The reactionwas heated to reflux for 2.5 h before cooling and removal of solvent.The residue was dissolved in ethyl acetate and washed rapidly with 1.3NHCl (40 ml). The acidic layer was then extracted with ethyl acetate(3×20 ml) and the combined organic layers washed with brine beforedrying over magnesium sulfate, filtering and re-moval of solvent invacuo. The desired product (5.9 g, 94%) was isolated as a pale yellowoil.

¹H NMR (400 MHz, CDCl₃); 1.5 (m, 9H), 2.8–3.2 (m, 2H), 4.2 (m, 2H),4.5–4.7 (m, 3H), 5.25 (m, 2H), 5.9 (m, 1H), 11.1 (broad S, 1H).

Intermediate 10: 1-[(aminooxy)methyl]-4-methoxybenzene

A solution was made of Boc hydroxylamine (2.0 g, 17.1 mmol) in dry THF(60 ml). Sodium hydride (1.1 g of a 60% suspension in paraffin oil, 25.7mmol) was then added and the suspension stirred. A catalytic amount ofKI was then added to the reaction prior to the cautious addition of4-methoxybenzyl chloride (3.2 g, 20.4 mmol). The reaction was thenallowed to stir overnight before removal of solvent in vacuo. Theresidue was taken up with diethyl ether (100 ml) and HCl gas bubbled infor 20 minutes, causing the start of precipitation of the product. Theflask was stoppered and left to stand overnight. The product was thenfiltered off as a off-white wax (39–52% yield according to varyingbatches).

¹H NMR (400 MHz, D₂O); 3.8 (s, 3H), 5 (s, 2H), 7.0 (d, 2H), 7.4 (d, 2H).

Intermediate 11:(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidine-carboxylicacid

The same method as employed in the preparation of Intermediate 7, butstarting from (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylicacid (Intermediate 1) and 1-[(aminooxy)methyl]-4-methoxy-benzene(Intermediate 10) gave the title compound as a gum in a 85% yield.

¹H NMR (400 MHz, DMSO); 1.5 (m, 9H), 2.7–2.9 (m, 1H) 3.9 (s, 3H), 4.2(m, 3H), 4.6 (m, 1H), 5.15 (s, 2H), 7.1 (d, 2H), 7.45 (d, 2H).

Intermediate 12: 2-aminoethyl acetate, TFA-salt

A solution was made containing ethanolamine (36.5 ml, 0.6 mol) inchloroform (1000 ml). The Boc₂O (13.1 g, 60 mmol) dissolved inchloroform (600 ml) was slowly added dropwise at 0° C. over a 6-hoursperiod (the temperature was maintained all over this period). Thereaction was allowed to reach room temperature and was stirredovernight. The organic layer was washed with water (2×500 ml), brine anddried over magnesium sulfate before being concentrated in vacuo. Thedesired product (9.5 g, >95%) was isolated as a colourless oil and wasused without further purification. A solution was made containing theBoc-ethanolamine (1.92 g, 12 mmol) with potassium carbonate (5 g, 36mmol) in DCM (40 ml). Acetyl chloride (30 ml, 0.42 mol) was added andthe reaction stirred for 6 hours at room temperature. The excess ofacetyl chloride was removed in vacuo and the crude dissolved in DCM(100ml). The organic layer was washed with water (50 ml), brine and driedover magnesium sulfate before being concentrated in vacuo. The desiredproduct (1.86 g, 77%) was isolated as a colourless oil and was usedwithout further purification. A solution was made containing the O-acyl,Boc-ethanolamine (1.65 g, 8.1 mmol) in DCM (20 ml) and TFA (20 ml) wasadded. After one hour at room temperature, the solvent was removed invacuo. The crude was concentrated from methanol (2–3 times) and from DCM(2–3 times) to give the expected compound (1.75 g, quant.) as an oilused without further purification.

¹H NMR (400 MHz, D₂O); 2.0 (m, 9H), 3.1–3.2 (m, 2H), 4.15–4.25 (m, 2H).

Intermediate 13: 2′-methyl[1,1′-biphenyl]-4-carboxylic acid

To a mixture of 4-bromobenzoic acid (30 g, 0.15 mol),2-methylphenylboronic acid (24 g, 0.15 mol), sodium carbonate (250 g) intoluene (500 mL) and water (500 mL) was added tetrakistriphenylphosphinepalladium(0) (9 g, 0.0074 mol) under nitrogen atmosphere. The reactionmixture was refluxed for 10 h. After this time, 100 ml of 10% NaOH wereadded to the reaction mixture, the aqueous layer was separated andwashed with toluene (2×200 mL). Acidification of the aqueous layer with3N HCl solution gave a solid product, which was filtered, washed withwater and dried. The crude product was then crystallised from toluene toyield 2′-methyl[1,1′-biphenyl]-4-carboxylic acid (20 g, 62.5%).Conversely, the product could also be obtained froml-bromo-2-methylbenzene and 4-carboxybenzeneboronic acid, usinganalogous conditions.

¹H NMR (300 MHz, DMSO); 2.2 (s, 3H), 7.2–7.4 (m, 4H), 7.43 (d, J=9 Hz,2H), 7.99 (d, J=9 Hz, 2H), 13 (b, 1H).

(In Red: No CAS-number)

Similarly, using the appropriate commercial boronic acids andarylbromides, the following, related intermediates were obtained:4′-methyl[1,1′-biphenyl]-4-carboxylic acid;2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid;2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid;2-methyl[1,1′-biphenyl]-4-carboxylic acid;3-methyl[1,1′-biphenyl]-4-carboxylic acid;2,2′-dimethyl[1,1′-biphenyl]4-carboxylic acid;2′-methoxy[1,1′-biphenyl]-4-carboxylic acid;3′-methoxy[1,1′-biphenyl]-4-carboxylic acid;4′-methoxy[1,1′-biphenyl]-4carboxylic acid;2′-chloro[1,1′-biphenyl]-4-carboxylic acid;3′-chloro[1,1′-biphenyl]-4-carboxylic acid;4-chloro[1,1′-biphenyl]-4-carboxylic acid;3′,4′-dichloro[1,1′-biphenyl]-4-carboxylic acid;2′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid;3′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid;2′-cyano[1,1′-biphenyl]-4-carboxylic acid;2′,4′-difluoro[1,1′-biphenyl]-4-carboxylic acid; 4-(2-pyridinyl)benzoicacid; 4-(3-pyridinyl)benzoic acid; 4-(4-pyridinyl)benzoic acid;4-(5-pyrimidinyl)benzoic acid; and others.

Intermediate 14: 4-(3-methyl-2-pyridinyl)benzoic acid

A mixture of 2-bromo-3-methylpyridine (22.5 g, 0.1312 mol),4-(hydroxymethyl)phenylboronic acid (25 g, 0.164 mol), Pd(PPh₃)₄ (9.5 g,0.0082 mol), and sodium carbonate (200 g in 500 ml of water) in toluene(750 ml) were refluxed under nitrogen atmosphere for 15 h. Separated thetoluene layer and distilled under reduced pressure to give a residue.The residue was then purified by column chromatography to yield[4-(3-methyl-2-pyridinyl)phenyl]methanol (12 g, 47%).

To a solution of [4-(3-methyl-2-pyridinyl)phenyl]methanol (12 g, 0.06mol) in dry DMF (150 mL) was added pyridiniumdichromate (91 g, 0.24 mol)and stirred at RT for 3days. The reaction mixture was poured into waterand extracted with ethyl acetate (250 mL). The organic layer was washedwith water, brine, dried and concentrated. The crude was purified bycolumn chromatography over silica gel to give4-(3-methyl-2-pyridinyl)benzoic acid (3 g, 25%) as white solid.

¹H NMR (300 MHz, DMSO); 2.3 (s, 3H), 7.33 (dd, J=7.5 Hz, 5 Hz, 1H), 7.67(d, J=8 Hz, 2H), 7.75 (d, J=7.5 Hz, 1H), 8.01 (d, J=8 Hz, 2H), 8.50 (d,J=5 Hz, 1H), 13 (b, 1H).

Intermediate 15: 4-(1-oxido-3-pyridinyl)benzoic acid

To a mixture of 4-tolylboronic acid (38 g, 0.28 mol), 3-bromopyridine(44 g, 0.28 mol), Na₂CO₃ (200 g) in toluene (500 ml) and water (500 ml)was added Pd(PPh₃)₄ (16 g, 0.014 mol), and refluxed for 16 h. Thereaction mixture was cooled, and the separated organic layer was washedwith water and brine, and dried. The solvent was removed to give4-(3-pyridyl)toluene (42 g, 90%). To a mixture of 4-(3-pyridyl)toluene(35 g, 0.207 mol) in pyridine (400 ml) and water (400 ml) was addedKMnO₄ (163 g, 1.03 mol) in portions and refluxed for 12 h. The reactionmixture was filtered through celite and acidified with conc. HCl. Theproduct was washed with water and dried to give 4-(3-pyridyl)benzoicacid (32 g, 76%) as a white solid. To a mixture of 4-(3-pyridyl)benzoicacid (22 g, 0.11 mol) in THF (2.51), mCPBA (152 g, 0.44 mol, 50%) wasadded and stirred at RT for 12 h. The solid was filtered, and washedwith THF to give 4-(1-oxido-3-pyridinyl)benzoic acid (20 g, 86%).

¹H NMR (300 MHz, DMSO); 7.5–7.8 (m, 5H), 7.9 (d, J=8Hz, 2H), 8.33 (d,J=5Hz, 2H.

Similarly, starting from 4-tolylboronic acid (45 g, 0.33 mol) and2-bromopyridine (52 g, 0.33 mol), the related intermediate4-(1-oxido-2-pyridinyl)benzoic acid was obtained.

Example 1 General Procedure for the Saponification of the Olefin-typeProline Methyl Esters, Such as Intermediates 3–6

A solution of sodium hydroxide (4.5 g, 112 mmol) in water (70 ml) wasadded to the relevant proline olefin methyl ester (66 mmol) in 3:1dioxane:water (500 ml) and the reaction stirred for 3 h. The reactionmixture was then washed with diethyl ether (2×50 ml), and the aqueousphase acidified to pH 2 (0.1N HCl) and extracted into ethyl acetate. Theethyl acetate layer was then dried over magnesium sulfate, filtered andthe solvent was then removed in vacuo to give the desired product innear quantitative yields as an oil which was used without furtherpurification.

Example 2 General Protocol for the Solution-phase Synthesis of OximetherPyrrolidine Derivatives of General Formula Ia (Scheme 1)

Method A: e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-methoxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

a) Protocol for the Formation of the Amide Bond

A solution was made containing the central building block, e.g.(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid (Intermediate 7) (1.5 g, 5.8 mmol), an amine or an amine salt, e.g.2-methoxy-ethylamine (0.51 ml, 5.81 mmol) and DMAP (780 mg, 5.8 mmol) inDCM (30 ml). At 0° C., EDC (1.1 g, 5.8 mmol) was slowly addedportion-wise. The reaction was slowly allowed to reach room temperatureand was stirred overnight. The DCM was evaporated and the crude purifiedby column chromatography using EtOAc (100%) to collect the desiredproduct, e.g. tert-butyl(2S,4EZ)-2-{[(2-meth-oxyethyl)amino]carbonyl}-4-(methoxyimino)-1-pyrrolidinecarboxylate(1.5 g, 80%) as a colourless oil.

¹H NMR (400 MHz, CDCl₃); 1.25 (m, 9H), 2.5–2.9 (m, 2H), 3.1 (s, 3H),3.2–3.3 (m, 4H), 3.65 (s, 3H), 3.8–4.4 (m, 3H), 6.7 (s broad, 1H).

b) Protocol for the N-deprotection Step

A solution was made containing the amide compounds from the previousstep, e.g. tert-butyl(2S,4EZ)-2-{[(2-methoxyethyl)amino]carbonyl}-4-(methoxyimino)-1-pyrrolidine-carboxylate(1.5 g, 0.4 mmol), in anhydrous ether (35 ml). HCl gas was bubbledslowly through the reaction and the deprotection was followed by TLC.After approximately 20 minutes, the ether was evaporated. The productwas concentrated in vacuo from DCM (2–3 times) to remove the HCl. Thedesired product, e.g.(2S,4EZ)-N-(2-methoxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(1.2 g, quant.) was isolated as a yellow oil and used without furtherpurification.

c) Protocol for the N-capping Step

A solution was made containing the free NH-compound from the previousstep, e.g.(2S,4EZ)-N-(2-methoxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(940 mg, 3.7 mmol), a carboxylic acid, e.g. [1,1′-biphenyl]-4-carboxylicacid (740 mg, 3.7 mmol) and DMAP (960 mg, 7.8 mmol) in DCM (30 ml). At0° C., EDC (715 mg, 3.7 mmol) was slowly added portionwise. The reactionwas slowly allowed to reach room temperature and was stirred overnight.The DCM was evaporated and the crude purified by column chromato-graphyusing EtOAc (100%) to collect the desired product, e.g.(2S,4EZ)-1-([1,1′-biphe-nyl]-4-ylcarbonyl)-N-(2-methoxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamideas a mixture of two isomers as an off-white solid.

1H NMR (400 MHz, CDCl3); 2.75–2.85 (m, 1H), 3.1–3.3 (m, 4H), 3.4–3.5 (m,4H), 3.8 (m, 3H), 4.1–4.3 (m, 2H), 5.1 (m, 1H), 6.9 (m, 1H), 7.2–7.7 (m,10H). M⁺ (APCI⁺); 396.

Method B: e.g. (2S,4E and4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

a) Protocol for the Formation of the Amide Bond

To a solution of the central building block, e.g.(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid (Intermediate 7) (24.2 mmol, 6.24 g) in dry THF (125 ml) at −25° C.was added NMM (2.5 eq, 60.4 mmol, 6.64 ml) followed byisobutylchloroformate (1.05 eq, 25.4 mmol, 3.3 ml). The resultingmixture was stirred at −25° C. for 30 min and an amine or an amine salt,e.g. (S)-2-amino-1-phenylethanol (1.51 eq, 36.5 mmol, 5 g) was thenadded. The mixture was allowed to gradually warm to rt. After 16 h, thesolvents were removed. The residue was dissolved in AcOEt, washed twicewith NH₄Cl saturated solution, then twice with 10% NaHCO₃ solution. Theorganic layer was dried over Na₂SO₄, filtrated and concentrated toafford the desired product, e.g. tert-butyl(2S,4EZ)-2-({[(2S)-2-hydroxy-2-phenylethyl]amino}carbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate(8.76 g, 96%) as a pale yellow oil in 88.5% purity by HPLC.

¹H NMR (CDCl₃: 300 MHz) δ 1.44 (s, 9H, N-Boc), 3.23–2.85 (m, 4H), 3.72(m, 1H), 3.85 (s, 3H, O—CH₃), 4.10 (m, 2H), 4.49 (m, 1H), 4.83 (m, 1H),7.34 (m, 5H, Ar—H); [M+Na⁺] (ESI⁺): 400.

b) Protocol for the N-deprotection Step

A solution was made containing the amide compounds from the previousstep, e.g. tert-butyl(2S,4EZ)-2-({[(2S)-2-hydroxy-2-phenylethyl]amino}carbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate(2.64 g, 7 mmol), in anhydrous DCM (35 ml). At 0° C., HCl gas wasbubbled slowly through the reaction and the deprotection was followed byTLC. After approximately 20 minutes, the DCM was evaporated. The productwas concentrated in vacuo from DCM (2–3 times) to remove the HCl. Thedesired product, e.g.(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(1.94 g, quant.) was isolated as a yellow solid and used without furtherpurification.

c) Protocol for the N-capping Step

To a suspension of 4-(2-methylphenyl)benzoic acid (1.49 g, 7 mmol.) in35 ml DCM, was added oxalyl chloride and DMF (3 ml) under ice cooling.The mixture was stirred for 2 h at rt. The solvent was removed affordingthe corresponding acyl chloride as a yellow solid. It was dissolved inDCM (30 mL) and added slowly on a 0° C. solution containing the freeNH-compound from the previous step, e.g.(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(1.94 g, 7 mmol), and triethylamine (5 eq, 35 mmol, 4.9 ml) in dry DCM(35 ml). The reaction mixture was stirred overnight at r.t. Poltrisaminewas added (2.12 g, 3.45 mmol/g) in order to scavenge excess of acylchloride. The mixture was shaken 3 h, filtered and the resultingsolution was washed with NH₄Cl sat, brine, and dried over Na₂SO₄. Afterfiltration and evaporation of the solvents, the resulting dark oil (3.26g) was purified by flash chromatography (Biotage system, column 40M, 90g SiO2, with gradients of DCM and MeOH as eluent), affording(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide.Separation of the E/Z-isomers was achieved by several chromatographies,affording(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(230 mg, colorless powder, 98.7% purity by HPLC) and(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(266 mg, colorless powder, 98.3% purity by HPLC).

(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide:Map. 74° C.; IR (neat) ν 3318, 2932, 1613, 1538, 1416, 1239, 1047, 848cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 2.27 (s, 3H, ArCH₃), 2.89 (dd, J=6, 12Hz, 1H), 3.18 (br d, J=12 Hz, 1H), 3.27 (m, 1H), 3.76 (m, 1H), 3.88 (s,3H, NOCH₃), 4.28 (d, J=10 Hz, 1H), 4.47 (d, J=10 Hz, 1H), 4.59 (br s,1H), 4.88 (m, 1H), 5.20 (m, 1H), 7.03–7.42 (m, 11H, H arom.), 7.45–7.54(m, 2H, H arom.); M⁺(APCI⁺): 472; M⁻(APCI⁻): 470. Analysis calculatedfor C₂₈H₂₉N₃O₄ 0.3 H₂O: C, 70.51; H, 6.26; N, 8.81. Found: C, 70.53; H,6.30; N, 8.87.

(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide:M.p. 78° C.; IR (neat) ν 3318, 2938, 1622, 1538, 1416, 1233, 1045, 852cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 2.28 (s, 3H, ArCH₃), 2.69 (dd, J=6, 10Hz, 1H), 3.02–3.22 (m, 2H), 3.25 (br s, 1H), 3.60 (m, 1H), 3.86 (s, 3H,NOCH₃), 4.14 (m, 2H), 4.71 (m, 1H), 4.96 (m, 1H), 7.03–7.42 (m, 11H, Harom.), 7.45–7.54 (m, 2H, H arom.); M⁺(APCI⁺): 472; M⁻(APCI⁻): 470.Analysis calculated for C₂₈H₂₉N₃O₄ 0.9 H₂O: C, 68.95; H, 6.36; N, 8.61.Found: C, 68.87; H, 6.25; N, 8.77.

d) E/Z-isomerisation

The pure E-isomer was isomerized to a mixture of the E/Z-isomers by thefollowing procedure: the E-isomer was dissolved in dioxane/water 3:1mixture. NaOH (1.7 eq; 0.52 mL of NaOH 1.6N) was added and the resultingsolution was stirred 2 h at r.t. The mixture was neutralysed with HCl0.1 N and lyophilised. The components of the resulting E/Z-mixture wereseparated and purified by flash chromatography using same conditions asdescribed above.

Example 3(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino)ethyl]-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 2, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4carboxylic acid, andN¹,N¹-diethyl-1,2-ethanediamine the title compound was obtained aftercolumn chromatography as an off-white solid as a mixture of E/Z-isomers.

1H NMR (400 MHz, CDCl3); 1.05–1.15 (m, 6H), 2.7–2.8 (m, 1H), 2.9–3.2 (m,6H), 3.4 (m, 1H), 3.6 (s, 3H), 4.0–4.1 (m, 1H), 4.3–4.4 (m, 1H), 3.75(m, 1H), 3.8 (m, 2H), 6.65 (m, 2H), 7.0–7.1 (m, 2H), 7.2–7.3 (m, 3H),7.35–7.45 (m, 6H), 8.8 (s/br, 0.5H). M⁺(APCI⁺); 543.

Example 4(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 2, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained aftercolumn chromatography as a mixture of E/Z-isomers as a off-white solid.The two isomers could be separated by another flash chromatographicpurification step.

(2S,4E)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide:1H NMR (400 MHz, CDCl3); 2.6–2.7 (m, 1H), 2.8–3.0 (m, 3H), 3.2 (m, 1H),3.4–3.6 (m, 1H), 3.9 (m, 1H), 4.15 (t, 1H), 4.6 (m, 1H), 4.85 (m, 1H),5.75 (s, 1H), 7.0–7.4 (m, 14H). M⁺(APCI⁺); 461.

(2S,4Z)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide:1H NMR (400 MHz, CDCl3); 2.5–2.6 (m, 1H), 2.7–2.9 (m, 1H), 3.0 (m, 1H),3.1–3.4 (m, 1H), 3.4–3.6 (m, 1H), 3.9–4.0 (m, 1H), 4.2–4.4 (m, 2H), 4.6(m, 1H), 4.8–4.9 (m, 1H), 5.75 (s, 1H), 7.0–7.5 (m, 14H). M⁺(APCI⁺);461.

Example 5(2S,4EZ)-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 2, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetic acid, and N¹,N¹-diethyl-1,2-ethanediamine the titlecompound was obtained after column chromatography as an off-white solidas a mixture of E/Z-isomers.

1H NMR (400 MHz, CDCl3); 0.9 (t, 3H), 1.0 (m, 3H), 2.6–3.1 (m, 7H), 3.15(m, 1H), 3.4 (m, 1H), 3.75 (s, 3H), 3.95 (t, 1H), 4.4–4.7 (m, 4H), 5.1(m, 1H), 7.0–7.3 (m, 10H), 9.1 (m, 1H). M⁺(APCI⁺); 451.

Example 6(2S,4EZ)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 2, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, phenoxyacetic acid, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained after column chromatography as an off-white solidas a mixture of E/Z-isomers. The isomers were then separated usingcolumn chromatography.

(2S,4E)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide:1H NMR (360MHz, CDCl₃); 1.2 (m, 6H), 2.7 (m, 1H), 3.35 (d, 1H), 4.1 (m,4H), 4.3 (d, 1H), 4.45 (d, 1H), 4.7 (m, 2H), 5.15 (d, 1H), 6.9–7.3 (m,10H), 7.9 (d, 1H), 8.15 (m, 1H), 9.0 (br s, 1H). M⁺(APCI⁺); 499.

(2S,4Z)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide:1H NMR (360MHz, CDCl₃); 1.2 (m, 6H), 2.7 (m, 1H), 3.2 (m, 1H), 4.1 (m,4H), 4.35 (m, 2H), 4.7 (m, 2H), 5.1 (m, 1H), 6.9–7.3 (m, 10H), 7.9 (d,1H), 8.15 (m, 1H), 9.0 (br s, 1H). M⁺(APCI⁺); 499.

Example 7(2S,4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 2, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carboxylic acid, and9-ethyl-9H-carbazol-3-amine the title compound was obtained after columnchromatography as an off-white solid as a mixture of E/Z-isomers. Theisomers were separated by column chromatography.

(2S,4E)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide:1H NMR (360MHz, CDCl₃); 0.8 (m, 6H), 1.2 (m. 6H), 2.5 (m, 2H), 3.0 (m,1H), 3.3 (m, 1H), 3.8 (s, 3H), 4.2 (m, 3H), 4.45 (m, 1H), 5.3 (m, 1H),6.1 (d, 1H), 7.1 (m, 1H), 7.2 (m, 1H), 7.3 (d, 1H), 7.35 (m, 1H), 7.55(m, 1H), 7.65 (m, 1H), 8.0 (d, 1H), 8.5 (m, 1H), 9.1 (br S, 1H).M⁺(ES⁺); 543.

(2S,4Z)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide:1H NMR (360MHz, CDCl₃); 0.8 (m, 6H), 1.2 (m. 6H), 2.5 (m, 2H), 3.05 (m,1H), 3.25 (m, 1H), 3.75 (s, 3H), 4.1 (m, 3H), 4.45 (d, 1H), 5.3 (d, 1H,6.1 (d, 1H), 7.1 (t, 1H), 7.2 (m, 1H), 7.3 (m, 1H), 7.4 (m, 1H), 7.6 (m,1H), 7.7 (m, 1H), 8.0 (d, 1H), 8.45 (m, 1H), 9.1 (m, 1H). M⁺(ES⁺); 543.

Example 8(2S,4EZ)-4-[(allyloxy)imino]-1-benzoyl-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 2, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, benzoic acid, and 9-ethyl-9H-carbazol-3-amine the title compoundwas obtained after column chromatography as an off-white solid as amixture of E/Z-isomers.

1H NMR (360MHz, CDCl₃); 1.2 (m, 3H), 2.8 (m, 1H), 3.35 (m, 1H), 4.2 (m,4H), 4.4 (m, 3H), 5.2 (m, 2H), 5.35 (m, 1H), 5.85 (m, 1H), 7.0–7.5 (m,5H), 7.9 (m, 3H), 8.1 (m, 2H), 8.3 (m, 1H), 9.2 (br s, 1H). M⁺(APCI⁺);481.

Example 9 General Protocol for the Solution-phase Synthesis of OximetherPyrrolidine Derivatives of General Formula I Containing AdditionalReactive Groups;(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

a) Protocol for the Formation of the Amide Bond

A solution was made containing the central building block, e.g.(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid (Intermediate 7) (575 mg, 2.2 mmol), the amine or amine saltcontaining the suitably protected reactive group, e.g. 2-aminoethylacetate (Intermediate 12) (480 mg, 2.2 mmol) and DMAP (870 mg, 7.1 mmol)in DCM (20 ml). At 0° C., EDC (427 mg, 2.2 mmol) was slowly addedportion-wise. The reaction was slowly allowed to reach room temperatureand was stirred overnight. The DCM was evaporated and the crude purifiedby column chromatography using EtOAc/Hexane: 55/45 to collect thedesired amide compound, e.g. tert-butyl(2S,4EZ)-2-({[2-(acetyloxy)ethyl]-amino}carbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate(373 mg, 49%) as an oil.

1H NMR (400MHz, CDCl3); 1.7 (m, 9H), 2.1–2.2 (m, 3H), 2.8–3.3 (m, 2H),3.7–3.8 (m, 2H), 4.0–4.1 (m, 3H), 4.2–4.8 (m, 5H), 7.3 (s broad, 1H).

b) Protocol for the N-deprotection Step

A solution was made containing the Boc-protected compound from theprevious step, e.g. tert-butyl(2S,4EZ)-2-({[2-(acetyloxy)ethyl]amino}carbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate(373 mg, 1.2 mmol) in anhydrous ether (40 ml). HCl gas was bubbledslowly through the reaction and the deprotection was followed by TLC.After approximately 20 minutes, the ether was evaporated. The productwas concentrated in vacuo from DCM (2–3 times) to remove the HCl. Thedesired free NH product, e.g.2-({[(2S,4EZ)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)ethyl acetate(300 mg, quant.) was isolated as a yellow oil and used without furtherpurification.

1H NMR (400MHz, D₂O); 1.75 (s, 3H), 2.55–2.65 (m, 1H), 2.8–3.3 (m, 3H),3.45–3.55 (m, 3H), 3.8–4.0 (m, 4H), 4.25–4.35 (m, 1H).

c) Protocol for the N-capping Step

A solution was made containing the amine-hydrochloride from the previousstep, e.g.2-({[(2S,4EZ)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)ethyl acetate(560 mg, 2 mmol) and an acid chloride, e.g. [1,1′-biphenyl]-4-carbonylchloride (433 mg, 2 mmol) in DCM (20 ml). Triethylamine (0.7 ml, 5 mmol)was added and the reaction stirred overnight at room temperature. TheDCM was evaporated and the crude purified by column chromatography usingEtOAc (100%) to collect the desired amide compound, e.g.2-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)ethylacetate (457 mg, 54%) as an oil.

1H NMR (400MHz, CDCl3); 1.9 (s, 3H), 2.7–2.8 (m, 1H), 3.2–3.6 (m, 3H),3.75–3.85 (m, 3H), 4.0–4.4 (m, 4H), 5.15–5.25 (m, 1H), 7.2–7.6 (m, 9H).

d) Protocol for the Deprotection of the Reactive Group

A solution was made containing the side-chain protected compound fromthe previous step, e.g.2-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)ethylacetate (450 mg, 10.6 mmol) in THF (10 ml). An aqueous solution (10 ml)of sodium hydroxide (75 mg, 19 mmol) with methanol (5 ml) was added andthe reaction stirred at room temperature for three hours. The solventwas removed in vacuo and the crude purified by column chromatographyusing THF (100%) to give the expected final product, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(300 mg, 75%) as a white solid.

1H NMR (400MHz, CDCl3); 2.85–3.0 (m, 1H), 3.3–3.6 (m, 3H), 3.7–3.8 (2H),3.85–3.95 (m, 3H), 4.2–4.5 (m, 2H), 5.15–5.25 (m, 1H), 7.2–7.9 (m, 9H).M⁺(APCI⁺); 382.

Example 10(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 9, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-amino-1-phenylethylacetate, the title compound was obtained after column chromatography asa mixture of E/Z-isomers as an off-white solid. The two isomers could beseparated by another flash chromatographic purification step.

(2S,4E)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide: 1H NMR (400MHz, CDCl3);2.75–2.9 (m, 1H), 3.1–3.25 (m, 2H), 3.35–3.6 (m, 1H), 3.7–3.8 (m, 1H),3.75 (s, 3H), 4.1–4.3 (m, 2H), 4.8 (m, 1H), 5.1 (dd, 1H), 7.1–7.6 (m,15H). M⁺(APCI⁺); 458.

(2S,4Z)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide:1H NMR (400MHz, CDCl3); 2.7–2.85 (m, 1H), 3.05–3.25 (m, 2H), 3.35 (m,1H), 3.65–3.8 (m, 1H), 3.8 (s, 3H), 4.15–4.25 (d, 1H), 4.25–4.4 (m, 1H),4.75 (m, 1H), 5.1 (dd, 1H), 7.15–7.6 (m, 15H). M⁺(APCI⁺); 458.

Example 11 General Protocol for the Solution-Phase Synthesis ofOximether Pyrrolidine Derivatives of General Formula Ib (Scheme 5);(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime

a) Protocol for the Formation of the Amide Bond

A solution was prepared containing the central building block, e.g.(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid (Intermediate 7) (2.1 g, 8.1 mmol), an ortho-substituted aromaticamine or amine salt, e.g. 1,2-benzenediamine (0.88 g, 8.1 mmol) and DMAP(1.59 g, 13.0 mmol). in dry dichloromethane (30 ml). This solution wascooled to 0° C. and treated with EDC (1.56 g, 8.2 mmol) before warmingto room temperature and stirring for 2 days. The solvent was removed invacuo and the product purified by silica gel chromatography, elutingwith a gradient of 30–80% ethyl acetate in hexane to give the desiredanilide product, e.g. tert-butyl(2S,4EZ)-2-[(2-aminoanilino)carbonyl]-4-(methoxyimino)-1-pyrrolidinecarboxylate2.8 g, 97% as a colourless foam.

1H NMR (360MHz, CDCl3); 1.7, (m, 9H), 2.5–3.5 (br, 4H), 3.4 (m, 1H), 4.0(m, 3H), 4.2–4.4 (m, 2H), 4.9 (m, 1H), 6.9–7.5 (m, 4H), 8.5 (br, 1H).

b) Protocol for the Formation of the Fused Heterocyclic Ring

A solution of the anilide compound from the previous step, e.g.tert-butyl(2S,4EZ)-2-[(2-aminoanilino)carbonyl]-4-(methoxyimino)-1-pyrrolidinecarboxylate(0.8 g, 2.3 mmol) in dichloromethane (30 ml) and acetic acid (3 ml) wasstirred at room temperature for 3 days. Saturated aqueous sodiumbicarbonate (7 ml) was added to the reaction, the organic phasecollected and dried over magnesium sulfate before filtering and removalof solvent in vacuo to give the desired product, e.g. tert-butyl(2S,4EZ)-2-(1H-benzimidazol-2-yl)-4-(methoxyimino)-1-pyrrolidinecarboxylate(740 mg, 97%) as an off-white foam.

1H NMR (360MHz, CDCl3); 1.5 (m, 9H), 3.1 (m, 1H), 3.8 (m, 3H) 3.9–4.3(m, 3H), 5.3 (m, 1H), 7.1–7.6 (m, 4H), 10–10.5 (br, 1H).

c) Protocol for the N-deprotection Step

Hydrogen chloride gas was bubbled into a solution of the fusedheterocyclic product from the previous step, e.g. tert-butyl(2S,4EZ)-2-(1H-benzimidazol-2-yl)-4-(methoxyimino)-1-pyrrolidinecarboxylate(740 mg, 2.2 mmol) in dry DCM (20 ml) for 30 min. The solvent wasremoved in vacuo to give the desired product, e.g.(3EZ,5S)-5-(1H-benzimidazol-2-yl)-3-pyrrolidinone O-methyloxime (0.58 g,99%), as a brown amorphous powder which was used without furtherpurification.

d) Protocol for the N-capping Step

A solution of the free NH product from the previous step, e.g.(3EZ,5S)-5-(1H-benzimida-zol-2-yl)-3-pyrrolidinone O-methyloxime (0.58g, 2.2 mmol) in dry dichloromethane (25 ml) was treated with an acidchloride, e.g. [1,1′-biphenyl]-4-carbonyl chloride (0.48 g, 2.2 mmol)and triethylamine (0.9 ml, 6.6 mmol). The resulting solution was thenstirred for 3 h at room temp before removal of solvent in vacuo and thedesired isomers were isolated by flash chromatography on silica gel,eluting with a gradient of ethyl acetate (10–80%) in hexane to give thetwo isomers (120 mg of the less polar and 400 mg of the more polar) ofthe desired product, e.g. (3E,5S)- and(3Z,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime, as off-white powders.

(3E,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime: 1H NMR (360MHz, CDCl3); 3.2, (m, 1H), 3.8 (s, 3H), 4.0(m, 1H), 4.3 (m, 2H), 6.0 (m, 1H), 6.0 (m, 1H), 7.2–7.7 (m, 13H), 10–11(br, 1H). M⁺(APCI⁺); 411.

(3Z,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime: 1H NMR (360MHz, CDCl₃); 3.1, (m, 1H), 3.8 (s, 3H), 3.9(m, 1H), 4.3 (m, 2H), 6.0 (m, 1H), 6.0 (m, 1H), 7.2–7.7 (m, 13H), 10–11(br, 1H). M⁺(APCI⁺); 411.

Example 12(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 1, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and1,2-benzenediamine, the title compound was obtained in 91% purity byHPLC. MS(ESI+): m/z=425.

Example 13(3EZ,5S)-5-(1-methyl-1H-benzimidazol-2-yl)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 11, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, andN¹-methyl-1,2-benzenediamine, the title compound was obtained in 83%purity by HPLC. MS(ESI+): m/z=439.

Example 14(3EZ,5S)-5-(7-hydroxy-1H-benzimidazol-2-yl)-1-[(2′-methyl[1,1′-biphenyl]4-yl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 11, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2,3-diaminophenol,the title compound was obtained in 91% purity by HPLC. MS(ESI+):m/z=441.

Example 15(3EZ,5S)-5-(3,4-dihydro-2-quinazolinyl)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 11, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and2-(aminomethyl)aniline, the title compound was obtained in 77% purity byHPLC. MS(ESI+): m/z=439.

Example 16(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(1-methyl-1H-benzimidazol-2-yl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 11, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, andN¹-methyl-1,2-benzenediamine, the title compound was obtained in 88%purity by HPLC. MS(ESI+): m/z=425.

Example 17 General Protocol for the Solution-Phase Synthesis of Oxime orHydrazone Pyrrolidine Derivatives of General Formula I (Scheme 6); (2S4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(hydroxyimino)-N-[(2RS)-2-hydroxy-2phenethyl]-2-pyrrolidinecarboxamide

a) Protocol for the Hydrolysis of the Oximether Group.

The starting oximether compounds, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide,were obtained following the general methods as outlined, e.g., inExample 2, 11 or 22. A solution was made containing the oximethercompound, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(64 mg, 0.14 mmol), paraformaldehyde powder (95%, 42 mg, 1.41 mmol) andAmberlyst 15 (30 mg) in acetone containing 10% of water (2 mL). Thereaction was stirred 4 h at 60° C. Insoluble materials were filtered offand washed with a small amount of acetone. The filtrate was concentratedand the residue was diluted with DCM (15 mL). The organic solution waswashed with brine (10 mL), dried over Na2SO₄, and concentrated. Thedesired ketocarbonyl product, e.g. (2S)-1-([1,1biphenyl]-4-ylcarbonyl)-N-[(2RS)-hydroxy-2-phenylethyl]-4-oxo-2-pyrrolidinecarboxamide(56 mg, 92%) was isolated as a yellow oil and used without furtherpurification.

b) Protocol for the formation of Oxime and/or Hydrazone Compounds

A solution was made containing the keto-pyrrolidine derivative from theprevious step, e.g.(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-oxo-2-pyrrolidinecar-boxamide(46 mg, 0.1 mmol) and hydroxylamine hydrochloride (12 mg, 0.17 mmol) inchloroform (1 ml) containing triethylamine (29 mg, 0.29 mmol). Thereaction mixture was then stirred at ambient temperature for one day,prior to removal of solvent. The resultant crude reaction mixture waspurified by column chromatography using DCM/MeOH (25:1) to collect thedesired product, e.g. (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(hydroxy-imino)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamideas a mixture of two isomers as an off-white solid (46 mg, 96% yield).

¹H NMR (300MHz, CDCl₃); 2.6–3.3 (m, 4H), 4.0–4.7 (m, 4H), 4.9 (m, 1H),5.5 (m, 1H), 7.1–7.5 (m, 8H), 7.6–7.8 (m, 5H), 8.1 (m, 1H), 10.9 (m,1H). M⁺(APCI⁺); 444.

Example 18(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(dimethylhydrazono)-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 17, starting from(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]4-oxo-2-pyrrolidinecarboxamideand N,N-dimethylhydrazine, the resultant crude reaction mixture waspurified by column chromatography using DCM/MeOH (30:1) to collect thedesired product, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(dimethylhydrazono)-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamideas a mixture of two isomers as a light yellow oil in 56% yield (90.2%purity by HPLC).

¹H NMR (300MHz, CDCl₃); 2.35–2.55 (br s, 3H), 2.40–2.60 (m, 1H),2.75–3.55 (m, 5H), 3.55–3.82 (m, 1H), 3.90–4.4 (m, 2H), 4.83 (m, 1H),4.93–5.35 (m, 1H), 7.18–7.49 (m, 9H), 7.49–7.68 (m, 5H). M⁺(APCI⁺); 471.M⁻(APCI⁻); 469.

Example 19(2S,4EZ)-1-(([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl-4-methylhydrazono)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 17, staring from(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-oxo-2-pyrrolidinecarboxamideand N-methylhydrazine, the resultant crude reaction mixture was purifiedby column chromatography using DCM/MeOH (30:1) to collect the desiredproduct, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-(methylhydrazono)-2-pyrrolidinecarboxamideas a mixture of two isomers as a colorless solid in 57% yield (95.2%purity by HPLC).

¹H NMR (300MHz, CDCl₃); 2.45–2.70 (m, 1H), 2.85 (br s, 3H, NNHCH₃),2.85–3.5 (m, 2H), 3.51–4.4 (m, 4H), 4.84 (br s, 1H, NNHMe), 4.95–5.35(m, 1H), 7.18–7.67 (m, 14H). M⁺(APCI⁺); 457. M⁻(APCI⁻); 455.

Example 20(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-hydrazono-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 17, starting from(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-oxo-2-pyrrolidinecarboxamideand hydrazine hydrate (4% in EtOH), the resultant crude reaction mixturewas purified by column chromatography using DCM/MeOH (30:1) to collectthe desired product, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-hydrazono-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamideas a mixture of two isomers as a colorless solid in 63% yield (95.3%purity by HPLC).

¹H NMR (300MHz, DMSO-d₆, 80° C.); 2.55 (dd, J=9.8; 17.6 Hz, 1H), 2.73(dd, J=9.8; 18.2 Hz, 1H), 3.28 (m, 2H), 4.12 (m, 2H), 4.61 (m, 1H), 4.85(m, 1H), 5.15 (m, 1H), 5.70 (br s, 2H, NH₂N═C), 7.17–7.43 (m, 6H),7.44–7.60 (m, 4H), 7.66–7.77 (m, 5H). M(APCI⁺); 443. M⁻(APCI⁻); 441.

Example 21(2S,4EZ)-4-(acetylhydrazono)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide

A hydrazono pyrrolidine derivative obtained by the general methodoutlined in Example 17, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4ylcarbonyl)-4-hydrazono-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide(51 mg, 0.111 mmol) was dissolved in pyridine (1 mL). Acetic anhydride(3 eq, 32 μl, 0.35 mmol) was added, and the mixture was stirredovernight. The solvent was evaporated and the resultant crude reactionmixture was purified by column chromatography using DCM/MeOH (20:1) tocollect the desired product, e.g.(2S,4EZ)-4-(acetylhydrazono)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamideas a mixture of two isomers as a colorless solid in 73% yield (98.4%purity by HPLC).

¹H NMR (300MHz, DMSO-d₆, 80° C.); 1.99 (br s, 3H, CH₃CON), 2.7–3.4 (m,5H), 4.26 (m, 2H), 4.63 (m, 1H), 4.89 (m, 1H), 5.15 (m, 1H), 7.18–7.44(m, 6H), 7.45–7.62 (m, 4H), 7.66–7.85 (m, 5H), 9.97 (br s, 1H, MeCONHN,major isomer), 10.04 (br s, 1H, MeCONHN, minor isomer). M⁺(ESI⁺); 485.M⁻(ESI⁻); 483.

Example 22 General Protocol for the Solid-phase Synthesis of PyrrolidineDerivatives of General Formula I.

a) Loading Step

Kaiser oxime resin (16.5 g, loading 1.57 mmol/g) was added to a solutionof the relevant pyrrolidine carboxylic acid building block (51.8 mmol)and diisopropylcarbodiimide (8.1 ml, 51.8 mmol) in dry dichloromethane(150 ml). The resulting suspension was shaken over-night beforefiltering at the pump and washing sequentially with DMF, DCM and finallydiethyl ether before drying at room temperature in vacuo.

b) N-deprotection Step

The resin obtained in the loading step was shaken with a 20% solution oftrifluoroacetic acid in dichloromethane (200 ml) for 30 minutes prior tofiltering at the pump and washing sequentially with aliquots of DMF, DCMand finally diethyl ether before drying at room temperature in vacuo.

c) N-capping Step

The resin from the previous step was transferred into a 96-wellfilter-plate (approx. 50 mg of dry resin/well) and each well treatedwith an N-reactive derivatising agent, e.g. with either of the followingsolutions:

-   a) an acid chloride (0.165 mmol) and diisopropylethylamine (0.165    mmol) in dry dichloromethane (1 ml), overnight-   b) an acid (0.165 mmol) and DIC (0.165 mmol) in, depending on the    solubility of the carboxylic acid, dry dichloromethane or NMP (1 ml)    overnight.-   c) an isocyanate (0.165 mmol) in dry THF (1 ml), overnight-   d) a sulfonyl chloride (0.165 mmol) and diisopropylethylamine (0.165    mmol) in NMP (1 ml), overnight-   e) a benzyl (alkyl) bromide (0.165 mmol) and diisopropylethylamine    (0.165 mmol) in NMP, (1 ml), overnight.-   f) a vinyl ketone (0.165 mmol) in THF, overnight-   g) diketene (0.165 mmol) in THF, overnight

The plate was then sealed and shaken overnight at ambient temperature.The resins were then filtered, washing the resin sequentially withaliquots of DMF, DCM and finally diethyl ether before drying at roomtemperature in vacuo.

d) Cleavage Step

A solution of amine (0.05 mmol) in 2% AcOH in dichloromethane (1 ml) wasadded to each well containing the resin from the previous step. Theplate was then sealed and shaken for two days at ambient temperature.The wells were then filtered into a collection plate and the solventremoved in a vacuum centrifuge to yield 2–3 mg of the correspondingproducts, generally obtained as oils. The products were characterised byLC (205 nm) and mass spectrometry (ES+). All of the following exampleswere identified based on the observation of the correct molecular ion inthe mass spectrum, and were shown to be at least 40% pure (usually60–95% pure) by LC.

Example 23(2S,4EZ)-N²-(2-hydroxyethyl)-4-(methoxyimino)-N¹-pentyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 2-aminoethanol the title compound wasobtained in 100% purity by LC/MS. MS(ESI+): m/z=315.2.

Example 24(2S,4EZ)-4-benzylidene-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino)-ethyl-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, andN1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 90%purity by LC/MS. MS(ESI+): m/z=482.4.

Example 25(2S,4EZ)-4-[(allyloxy)imino]-1-(4-cyanobenzoyl)-N-[2-(1H-pyrrol-1-yl)phenyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 2-(1H-pyrrol-1-yl)phenylamine thetitle compound was obtained in 51% purity by LC/MS. MS(ESI+): m/z=454.4.

Example 26(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(2-furylmethyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and2-furylmethylamine the title compound was obtained in 92% purity byLC/MS. MS(ESI+): m/z=574.4.

Example 27(2S,4EZ)-4methoxyimino)-N¹-(3-methoxyphenyl)-N²-thienylmethyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methoxybenzene, and 2-thienylmethylamine the titlecompound was obtained in 79% purity by LC/MS. MS(ESI+): m/z=403.2.

Example 28(2S,4EZ)-2-{[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]carbonyl}-4-(methoxyimino)-N-pentyl-1-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 1-(1,3-benzodioxol-5-ylmethyl)piperazinethe title compound was obtained in 72% purity by LC/MS. MS(ESI+):m/z=474.4.

Example 29(2S,4EZ)-4-[(benzyloxy)imino]-1-(4-cyanobenzoyl)-N-(2-furylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 2-furylmethylamine the title compoundwas obtained in 49% purity by LC/MS. MS(ESI+): m/z=443.4.

Example 30(2S,4EZ)-4-[(benzyloxy)imino]-N-[2-(diethylamino)ethyl]-1-(4-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and N1,N1-diethyl-1,2-ethanediamine thetitle compound was obtained in 86% purity by LC/MS. MS(ESI+): m/z=529.6.

Example 314-[((2S,4EZ)-4-[(benzyloxy)imino]-2-{[4-(3,4-dichlorophenyl)-1-piperazinyl]-carbonyl}pyrrolidinyl)carbonyl]benzonitrile

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4cyanobenzoyl chloride, and 1-(3,4-dichlorophenyl)piperazine thetitle compound was obtained in 43% purity by LC/MS. MS(ESI+): m/z=576.6.

Example 32(2S,4EZ)-4-(methoxyimino)-N¹-pentyl-N²-[2-(1H-pyrrol-1-yl)phenyl]-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 2-(1H-pyrrol-1-yl)phenylamine the titlecompound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=412.2.

Example 33(2S,4EZ)-1-acryloyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(2-furylmethyl-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, acryloyl chloride, and2-furylmethylamine the title compound was obtained in 74% purity byLC/MS. MS(ESI+): m/z=436.8.

Example 34(2S,4EZ)-4-(tert-butoxyimino)-N²-cyclopropyl-N¹-(3,5-dichlorophenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tertbutoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, 1,3-dichloro-5-isocyanatobenzene, and cyclopropylamine the titlecompound was obtained in 48% purity by LC/MS. MS(ESI+): m/z=427.6.

Example 35(2S,4EZ)-4-[(allyloxy)imino]-N-[2-(diethylamino)ethyl]-1-l(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, andN1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 93%purity by LC/MS. MS(ESI+): m/z=475.4.

Example 36(2S,4EZ)-N²-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-N¹-(3-methylphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tertbutoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methylbenzene, and (1RS)-2-amino-1-phenylethanolthe title compound was obtained in 100% purity by LC/MS. MS(ESI+):m/z=411.2.

Example 37(2S,4EZ)-1-[(benzoylamino)carbonyl]-N-benzyl-4-[(benzyloxy)imino]-N-methyl-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and N-benzyl-N-methylamine the title compoundwas obtained in 40% purity by LC/MS. MS(ESI+): m/z=485.4.

Example 38(2S,4EZ)-1-(4-cyanobenzoyl)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 72% purity by LC/MS. MS(ESI+): m/z=480.4.

Example 39(2S,4EZ)-4-(methoxyimino)-N¹-(3-methylphenyl)-N²-(2-thienylmethyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methylbenzene, and 2-thienylmethylamine the titlecompound was obtained in 98% purity by LC/MS. MS(ESI+): m/z=387.2.

Example 40(2S,4EZ)-4-(tert-butoxyimino)-N-(2-methoxyethyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and2-methoxyethylamine the title compound was obtained in 75% purity byLC/MS. MS(ESI+): m/z=450.2.

Example 41(3EZ,5S)-5-{[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]carbonyl}-1-benzoyl-3-pyrrolidinoneO-(3,4-dichlorobenzyl)oxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 1-(1,3-benzodioxol-5-ylmethyl)piperazine thetitle compound was obtained in 71% purity by LC/MS. MS(ESI+): m/z=609.8.

Example 42 tert-butyl3-[({(2S,4EZ)-4-(ethoxyimino)-1-(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]pyrrolidinyl}carbonyl)amino]-1-azetidinecarboxylate

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and tert-butyl3-amino-1-azetidinecarboxylate the title compound was obtained in 100%purity by LC/MS. MS(ESI+): m/z=519.6.

Example 43(2S,4EZ)-4-{[(4-methoxybenzyl)oxy]imino}-N-(3-methylphenyl)-2-(4-morpholinylcarbonyl)-1-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methylbenzene, and morpholine the title compoundwas obtained in 41% purity by LC/MS. MS(ESI+): m/z=467.4.

Example 44(2S,4EZ)-N²-cyclopropyl-4-{[(4-methoxybenzyl)oxy]imino}-N¹-pentyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and cyclopropylamine the title compound wasobtained in 75% purity by LC/MS. MS(ESI+): m/z=417.2.

Example 45(3EZ,5S)-5-{4-(3,4-dichlorophenyl)-1-piperazinyl]carbonyl}-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-3-pyrrolidinoneO-benzyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and1-(3,4-dichlorophenyl)piperazine the title compound was obtained in 47%purity by LC/MS. MS(ESI+): m/z=639.8.

Example 46 (2S,4EZ)-4-(tert-butoxyimino)-N-[2-(1H-pyrrol1-yl)phenyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, and 2-(1H-pyrrol-1-yl)phenylamine the title compound was obtainedin 83% purity by LC/MS. MS(ESI+): m/z=341.2.

Example 471-({(2S,4EZ)-4-(chloromethylene)-1-[(4-chlorophenoxy)acetyl]pyrrolidinyl}carbonyl)-4-(3,4-dichlorophenyl)piperazine

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, (4-chlorophenoxy)acetyl chloride, and1-(3,4-dichlorophenyl)piperazine the title compound was obtained in 64%purity by LC/MS. MS(ESI+): m/z=543.6.

Example 48(2S,4EZ)-4-[(benzyloxy)imino]-N-(4,6-dimethoxy-2-pyrimidinyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, staring from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and4,6-dimethoxy-2-pyrimidinamine the title compound was obtained in 62%purity by LC/MS. MS(ESI+): m/z=564.6.

Example 49(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-[4-(dimethylamino)butanoyl]-N-(1-naphthylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4dichlorobenzyl)oxy]imino})-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)butanoyl chloride, and 1-naphthylmethylamine thetitle compound was obtained in 62% purity by LC/MS. MS(ESI+): m/z=555.6.

Example 50(2S)-N²-(2,1,3-benzothiadiazol-4-yl)-N¹-(3,5-dichlorophenyl)-4-oxo-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-oxoproline, 1,3-dichloro-5-isocyanatobenzene,and 2,1,3-benzothiadiazol-1-amine the title compound was obtained in 47%purity by LC/MS. MS(ESI+): m/z=450.6.

Example 51(2S,4EZ)-N-benzyl-4-(chloromethylene)-N-methyl-1-(4-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and N-benzyl-N-methylamine the titlecompound was obtained in 61% purity by LC/MS. MS(ESI+): m/z=461.4.

Example 52(2S,4EZ)-N²-(9-ethyl-9H-carbazol-3-yl)-4-{[(4-methoxybenzyl)oxy]imino}-N¹-(3-methylphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocya-nato-3-methylbenzene, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 72% purity by LC/MS. MS(ESI+): m/z=590.8.

Example 53(2S)-N-(tert-butyl)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and tert-butylamine thetitle compound was obtained in 100% purity by LC/MS. MS(ESI+):m/z=375.4.

Example 54(2S,4EZ)-4-benzylidene-1-[4-(dimethylamino)butanoyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)butanoyl chloride, and 6-quinolinamine the titlecompound was obtained in 71% purity by LC/MS. MS(ESI+): m/z=443.6.

Example 55(2S)-1-[4-(dimethylamino)butanoyl]-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, 4-(dimethylamino)butanoylchloride, and 9-ethyl-9H-carbazol-3-amine the title compound wasobtained in 51% purity by LC/MS. MS(ESI+): m/z=433.6.

Example 56(2S,4EZ)-N-(1,3-benzodioxol-5-ylmethyl)-4-[benzyloxy)imino]-1-(4-cyanobenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 1,3-benzodioxol-5-ylmethylamine thetitle compound was obtained in 51% purity by LC/MS. MS(ESI+): m/z=497.6.

Example 57(2S)-1-({1-[4-(dimethylamino)butanoyl]-4-methylene-2-pyrrolidinyl}carbonyl)-3-azetidinol

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, 4-(dimethylamino)butanoylchloride, and 3-azetidinol the title compound was obtained in 100%purity by LC/MS. MS(ESI+): m/z=296.4.

Example 58(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[2-(1H-pyrrol-1-yl)phenyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in 54%purity by LC/MS. MS(ESI+): m/z=623.6.

Example 59(2S,4EZ)-4-benzylidene-1-[(4-chlorophenoxy)acetyl]-N-(3,4dimethoxybenzyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, (4-chlorophenoxy)acetyl chlo-ride, and 3,4-dimethoxybenzylaminethe title compound was obtained in 49% purity by LC/MS. MS(ESI+):m/z=521.6.

Example 60(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(diphenylacetyl)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 2-thienylmethylamine the titlecompound was obtained in 51% purity by LC/MS. MS(ESI+): m/z=592.6.

Example 61(2S,4EZ)-N-(3,4-dimethoxybenzyl)-1-(diphenylacetyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 3,4-dimethoxybenzylamine the titlecompound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=502.6.

Example 62(2S,4EZ)-N¹-(3,5-dichlorophenyl)-4-(ethoxyimino)-N²-[2-(1H-pyrrol-1-yl)phenyl]-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 1,3-dichloro-5-isocyanatobenzene, and2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in 54%purity by LC/MS. MS(ESI+): m/z=500.6.

Example 63(2S,4EZ)-N²-(1,3-benzodioxol-5-ylmethyl)-4-{[(4-methoxybenzyl)oxy]imino}-N¹-pentyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 1,3-benzodioxol-5-ylmethylamine the titlecompound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=511.4.

Example 64(2S,4EZ)-N-benzyl-4-[(benzyloxy)imino]-1-(diphenylacetyl)-N-methyl-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and N-benzyl-N-methylamine the titlecompound was obtained in 42% purity by LC/MS. MS(ESI+): m/z=532.4.

Example 65(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and2,1,3-benzothiadiazol-4-amine the title compound was obtained in 66%purity by LC/MS. MS(ESI+): m/z=472.4.

Example 66(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 6-quinolinamine the titlecompound was obtained in 79% purity by LC/MS. MS(ESI+): m/z=465.4.

Example 67(2S,4EZ)-1-acetoacetyl-N-benzyl-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2,4-oxetanedione, and benzylamine the title compound was obtainedin 45% purity by LC/MS. MS(ESI+): m/z=332.2.

Example 68(2S,4EZ)-1-(1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-furylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbo-nyl chloride, and 2-furylmethylamine thetitle compound was obtained in 70% purity by LC/MS. MS(ESI+): m/z=421.4.

Example 69(2S,4EZ)-1-[(4-chlorophenoxy)acetyl]-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, (4-chlorophenoxy)acetyl chloride, and(1RS)-2-amino-1-phenylethanol the title compound was obtained in 62%purity by LC/MS. MS(ESI+): m/z=590.8.

Example 70(2S,4EZ)-N-allyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and allylamine the titlecompound was obtained in 87% purity by LC/MS. MS(ESI+): m/z=378.2.

Example 71(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-thienylmethylamine thetitle compound was obtained in 78% purity by LC/MS. MS(ESI+): m/z=434.4.

Example 72(2S,4EZ)-4-(cyanomethylene)-N-(2-furylmethyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and2-furylmethylamine the title compound was obtained in 34% purity byLC/MS. MS(ESI+): m/z=424.4.

Example 73(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-furylmethylamine thetitle compound was obtained in 75% purity by LC/MS. MS(ESI+): m/z=418.4.

Example 74(2S,4EZ)-1-acetyl-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, acetyl chloride, and cyclopropylamine the title compound wasobtained in 52% purity by LC/MS. MS(ESI+): m/z=384.4.

Example 75(2S,4EZ)-N-(2-furylmethyl)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and2-furylmethylamine the title compound was obtained in 62% purity byLC/MS. MS(ESI+): m/z=430.4.

Example 76(2S,4EZ)-N-benzyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-methyl-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and N-benzyl-N-methylaminethe title compound was obtained in 67% purity by LC/MS. MS(ESI+):m/z=442.4.

Example 77(2S,4EZ)-1-(diphenylacetyl)-4-(ethoxyimino)-N-(2-thienylmethyl-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 2-thienylmethylamine the titlecompound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=462.4.

Example 78(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl-4-(cyanomethylene)-1-(diphenylacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 2,1,3-benzothiadiazol-4-amine thetitle compound was obtained in 42% purity by LC/MS. MS(ESI+): n/z=480.4.

Example 79(2S)-1-(diphenylacetyl)-N-(1-naphthylmethyl)-4-oxo-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-oxoproline, diphenylacetyl chloride, and1-naphthylmethylamine the title com-pound was obtained in 60% purity byLC/MS. MS(ESI+): m/z=463.4.

Example 80(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-(diphenylacetyl-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 1,2-benzenediamine the title compoundwas obtained in 72% purity by LC/MS. MS(ESI+): m/z=425.4.

Example 81(2S)-2-[1-([1,1′-biphenyl]-4-ylcarbonyl)-4-methylene-2-pyrrolidinyl]-1H-benzimidazole

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonylchloride, and 1,2-benzenedi-amine the title compound was obtained in 73%purity by LC/MS. MS(ESI+): m/z=380.4.

Example 82(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-methoxyethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-methoxyethylamine thetitle compound was obtained in 55% purity by LC/MS. MS(ESI+): m/z=399.6.

Example 83(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-(diphenylacetyl)-3-pyrrolidinoneO-allyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 1,2-benzenediamine the title compoundwas obtained in 63% purity by LC/MS. MS(ESI+): m/z=451.4.

Example 84(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, andN1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 90%purity by LC/MS. MS(ESI+): mz=437.4.

Example 85(2S,4EZ)-1-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 2-thienylmethylamine the titlecompound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=554.4.

Example 86(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(3,4-dimethoxybenzyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 3,4-dimethoxybenzylaminethe title compound was obtained in 58% purity by LC/MS. MS(ESI+):m/z=488.4.

Example 87(2S,4EZ)-1-acetoacetyl-4-(methoxyimino)-N-(1-naphthylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2,4-oxetanedione, and 1-naphthylmethylamine the title compound wasobtained in 40% purity by LC/MS. MS(ESI+): m/z=382.2.

Example 88(2S,4EZ)-N-allyl-4-{[(3,4-dichlorobenzyl)oxy]imino}1-(diphenylacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and allylamine the title compound wasobtained in 54% purity by LC)MS. MS(ESI+): m/z=536.6.

Example 89(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N¹-pentyl-N²-(6-quinolinyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 6-quinolinamine the title compound wasobtained in 54% purity by LC/MS. MS(ESI+): m/z=542.6.

Example 90(2S,4EZ)-4-(chloromethylene)-1-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and (1RS)-2-amino-1-phenylethanol thetitle compound was obtained in 87% purity by LC/MS. MS(ESI+): m/z=475.4.

Example 91(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonylchloride, and 2-amino-1-phenylethanol the title compound was obtained in74% purity by LC/MS. MS(ESI+): m/z=427.4.

Example 92(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbo-nyl chloride, and 6-quinolinamine thetitle compound was obtained in 73% purity by LC/MS. MS(ESI+): m/z=468.4.

Example 93(2S,4EZ)-4-benzylidene-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and N1,N1-diethyl-1,2-ethanediamine thetitle compound was obtained in 71% purity by LC/MS. MS(ESI+): m/z=496.4.

Example 94(2S,4EZ)-1-acetoacetyl-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2,4-oxetanedione, and 2-thienylmethylamine the title compound wasobtained in 42% purity by LC/NS. MS(ESI+): m/z=338.2.

Example 95(2S,4EZ)-1-acetyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(2-hydroxy-2-phenylethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, acetyl chloride, and (1RS)-2-amino-1-phenylethanol the titlecompound was obtained in 48% purity by LC/MS. MS(ESI+): m/z=464.6.

Example 96(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N¹-(3,5-dichlorophenyl)-N²-(6-quinolinyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1,3-dichloro-5-isocyanatobenzene, and 6-quinolinamine the titlecompound was obtained in 66% purity by LC/MS. MS(ESI+): m/z=617.2.

Example 97(2S,4EZ)-4-(methoxyimino)-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 1-naphthylmethylamine the titlecompound was obtained in 99% purity by LC/MS. MS(ESI+): m/z=432.2.

Example 98(2S,4EZ)-4-(chloromethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and3,4-dimethoxybenzylamine the title compound was obtained in 51% purityby LC/MS. MS(ESI+): m/z=503.4.

Example 99(2S,4EZ)-1-(diphenylacetyl)-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 2-thienylmethylamine the titlecompound was obtained in 88% purity by LC/MS. MS(ESI+): m/z=448.4.

Example 100(2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and benzylamine the title compound wasobtained in 82% purity by LC/MS. MS(ESI+): m/z=442.4.

Example 101(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[2-(diethylamino)ethyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, andN1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 74%purity by LC/MS. MS(ESI+): m/z=581.6.

Example 102(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-[4-(dimethylamino)butanoyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 4(dimethylamino)butanoyl chloride, and 6-quinolinamine the titlecompound was obtained in 95% purity by LC/MS. MS(ESI+): m/z=542.6.

Example 103(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and5-ethyl-1,3,4-thiadiazol-2-amine the title compound was obtained in 89%purity by LC/MS. MS(ESI+): m/z=450.2.

Example 104(2S,4EZ)-N-benzyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-4(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]4-carbonyl chloride, and benzylamine the titlecompound was obtained in 72% purity by LC/MS. MS(ESI+): m/z=428.2.

Example 105(2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-(ethoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and benzylamine the title compound wasobtained in 53% purity by LC/MS. MS(ESI+): m/z=456.4.

Example 106(2S,4EZ)-N²-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N¹-(3-methoxyphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methoxybenzene, and cyclopropylamine the titlecompound was obtained in 45% purity by LC/MS. MS(ESI+): m/z=491.6.

Example 107(2S,4EZ)-1-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-{[(4-methoxyben-zyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and (1RS)-2-amino-1-phenylethanol thetitle compound was obtained in 66% purity by LC/MS. MS(ESI+): m/z=578.4.

Example 108(2S)-N-(2-furylmethyl)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 2-furylmethylamine thetitle compound was obtained in 43% purity by LC/MS. MS(ESI+): m/z=399.2.

Example 109(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-(diphenylacetyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 2,1,3-benzothiadiazol-4-amine thetitle compound was obtained in 69% purity by LC/MS. MS(ESI+): mz=486.4.

Example 110(2S)-N1-(3,5-dichlorophenyl)-N2-(3,4-dimethoxybenzyl)-4-oxo-1,2-pyrrolidine-dicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-oxoproline, 1,3-dichloro-5-isocyanatobenzene,and 3,4-dimethoxybenzylamine the title compound was obtained in 48%purity by LC/MS. MS(ESI+): m/z=466.6.

Example 111(2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and benzylamine the title compound wasobtained in 60% purity by LC/MS. MS(ESI+): m/z=548.4.

Example 112(2S,4EZ)-1-benzoyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 6-quinolinamine the title compound wasobtained in 67% purity by LC/MS. MS(ESI+): m/z=533.6.

Example 113(2S,4EZ)-1-acetoacetyl-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 2,4-oxetanedione, and cyclopropylamine the title compound wasobtained in 76% purity by LC/MS. MS(ESI+): m/z=426.6.

Example 114(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N²-[(2RS)-2-hydroxy-2-phenethyl]-N¹-pentyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and (1RS)-2-amino-1-phenylethanol the titlecompound was obtained in 47% purity by LC/MS. MS(ESI+): m/z=535.6.

Example 115(2S,4EZ)-4-[(benzyloxy)imino]-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 1-naphthylmethylamine the titlecompound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=508.4.

Example 116(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4methylene-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonylchloride, and 6-quinolinamine the title compound was obtained in 88%purity by LC/MS. MS(ESI+): m/z=434.2.

Example 117(2S,4EZ)-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(diphenylacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and cyclopropylamine the title compoundwas obtained in 49% purity by LC/MS. MS(ESI+): m/z=536.6.

Example 118(2S,4EZ)-1-(4-cyanobenzoyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 6-quinolinamine the title compoundwas obtained in 52% purity by LC/MS. MS(ESI+): m/z=558.6.

Example 119(2S)-4-oxo-1-(phenoxyacetyl)-N-[2-(1H-pyrrol-1-yl)phenyl]-2-pyrrolidinecarbox-amide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-oxoproline, phenoxyacetyl chloride, and2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in 42%purity by LC/MS. MS(ESI+): m/z=404.2.

Example 120(2S,4EZ)-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(methoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and cyclopropylamine the title compoundwas obtained in 54% purity by LC/MS. MS(ESI+): m/z=414.6.

Example 121(2S,4EZ)-N-(1,3-benzodioxol-5-ylmethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]4-carbonyl chloride, and1,3-benzodioxol-5-ylmethylamine the title compound was obtained in 64%purity by LC/MS. MS(ESI+): m/z=472.4.

Example 122(3EZ,5S)-5-[(4-acetyl-1-piperazinyl)carbonyl]-1-acryloyl-3-pyrrolidinoneO-(3,4-dichlorobenzyl)oxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, acryloyl chloride, and 1-acetylpiperazine the title compound wasobtained in 79% purity by LC/MS. MS(ESI+): m/z=467.6.

Example 123(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonylchloride, and 2-furylmethylamine the title compound was obtained in 94%purity by LC/MS. MS(ESI+): m/z=387.2.

Example 124(2S,4EZ)-4-(cyanomethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and3,4-dimethoxybenzylamine the title compound was obtained in 65% purityby LC/MS. MS(ESI+): m/z=494.4.

Example 125(2S,4EZ)-1-[(benzoylamino)carbonyl]-4-(cyanomethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=492.4.

Example 126(2S,4EZ)-1-benzoyl-N-[2-(diethylamino)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and N1,N1-diethyl-1,2-ethanediamine the titlecompound was obtained in 80% purity by LC/MS. MS(ESI+): m/z=361.2.

Example 127(2S,4EZ)-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-4-(ethoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and N1,N1-diethyl-1,2-ethanediamine thetitle compound was obtained in 50% purity by LC/MS. MS(ESI+): m/z=465.4.

Example 128(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-4-[(benzyloxy)imino]-1-(4-cyanobenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 2,1,3-benzothiadiazol-4-amine thetitle compound was obtained in 55% purity by LC/MS. MS(ESI+): m/z=497.4.

Example 129(2EZ)-[5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinylidene]ethanenitrile

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]4-carbonyl chloride, and 1,2-benzenediamine thetitle compound was obtained in 70% purity by LC/MS. MS(ESI+): m/z=405.2.

Example 130(2S,4EZ)-4-(chloromethylene)-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=488.6.

Example 131(2S)-N²-(9-ethyl-9H-carbazol-3-yl)-N¹-(3-methoxyphenyl)-4-methylene-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,1-isocyanato-3-methoxybenzene, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 47% purity by LC/MS. MS(ESI+): m/z=469.4.

Example 132(2S,4EZ)-4-(cyanomethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in36% purity by LC/MS. MS(ESI+): m/z=345.2.

Example 133(2S,4EZ)-1-(4-cyanobenzoyl)-N-[2-(diethylamino)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and N1,N1-diethyl-1,2-ethanediamine thetitle compound was obtained in 58% purity by LC/MS. MS(ESI+): m/z=386.2.

Example 1344-{[(2S,4EZ)-2-(1H-benzimidazol-2-yl)-4-(cyanomethylene)pyrrolidinyl]carbonyl}benzonitrile

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 1,2-benzenediamine the title compoundwas obtained in 84% purity by LC/MS. MS(ESI+): m/z=354.2.

Example 135(2S,4EZ)-4-[(allyloxy)imino]-1-[4-(dimethylamino)butanoyl]-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)-butanoyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 40%purity by LC/MS. MS(ESI+): m/z=490.4.

Example 136(2S,4EZ)-4-benzylidene-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in53% purity by LC/MS. MS(ESI+): m/z=396.2.

Example 137(2S,4EZ)-4-benzylidene-1-[4-(dimethylamino)butanoyl]-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)butanoyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 74%purity by LC/S. MS(ESI+): m/z=509.4.

Example 138(2S,4EZ)-4-(chloromethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in73% purity by LC/MS. MS(ESI+): m/z=354.4.

Example 139(2S)-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 71%purity by LC/MS. MS(ESI+): m/z=320.2.

Example 140(2S,4EZ)-4-(cyanomethylene)-N-(9-ethyl-9H-carbazol-3-yl)-1-(4-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chlo-ride, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 37% purity by LC/MS. MS(ESI+): m/z=541.4.

Example 141N-{[(2S,4EZ)-2-(1H-benzimidazol-2-yl)-4-(chloromethylene)pyrrolidinyl]carbon}benzamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and 1,2-benzenediamine the title compound wasobtained in 51% purity by LC/MS. MS(ESI+): m/z=381.4.

Example 142(2S)-N¹-(3,5-dichlorophenyl)-N²-(9-ethyl-9H-carbazol-3-yl)-4-methylene-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,1,3-dichloro-5-isocyanatobenzene, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 40% purity by LC/MS. MS(ESI+): m/z=507.6.

Example 143(2S)-1-(diphenylacetyl)-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, diphenylacetyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 42%purity by LC/MS. MS(ESI+): m/z=514.4.

Example 144(2S,4EZ)-1-benzoyl-4-(chloromethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 48% purity by LC/MS. MS(ESI+): m/z=458.4.

Example 145(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(cyanomethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 32%purity by LC/MS. MS(ESI+): m/z=525.4.

Example 146(2S,4EZ)-4-(cyanomethylene)-N-(9-ethyl-9H-carbazol-3-yl)-1-(3-oxobutyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, 3-buten-2-one, and 9-ethyl-9H-carbazol-3-amine the title compoundwas obtained in 59% purity by LC/MS. MS(ESI+): m/z=415.2.

Example 147(2S)-1-[(4-chlorophenoxy)acetyl]-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, (4-chlorophenoxy)acetylchloride, and 9-ethyl-9H-carbazol-3-amine the title compound wasobtained in 100% purity by LC/MS. MS(ESI+): m/z=488.4.

Example 148(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, staring from1-(tert-butoxycarbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonylchloride, and 9-ethyl-9H-carbazol-3-amine the title compound wasobtained in 46% purity by LC/MS. MS(ESI+): m/z=500.4.

Example 149 2-[(2S,4EZ)-4-(chloromethylene),prolidinyl]-1H-benzimidazole

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, and 1,2-benzenediamine the title compound was obtained in 43%purity by LC/MS. MS(ESI+): m/z=234.4.

Example 150(2S,4EZ-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in91% purity by LC/MS. MS(ESI+): m/z=365.2.

Example 151(2S)-1-benzoyl-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, benzoyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 52%purity by LC/MS. MS(ESI+): m/z=424.2.

Example 152(2S,4EZ)-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and N1,N1-diethyl-1,2-ethanediamine thetitle compound was obtained in 56% purity by LC/MS. MS(ESI+): m/z=557.4.

Example 144153(2S,4EZ)-1-benzoyl-N-(2-furylmethyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 2-furylmethylamine the title compound wasobtained in 40% purity by LC/MS. MS(ESI+): m/z=448.2.

Example 154(2S,4EZ)-4-(tert-butoxyimino)-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and N1,N1-diethyl-1,2-ethanediamine thetitle compound was obtained in 80% purity by LC/MS. MS(ESI+): m/z=493.4.

Example 155(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(3,4-dimethoxybenzyl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonylchloride, and 3,4-dimethoxybenzylamine the title compound was obtainedin 72% purity by LC/MS. MS(ESI+): m/z=457.2.

Example 156(2S,4EZ)-4-(cyanomethylene)-N¹-(3,5-dichlorophenyl)-N²-(9-ethyl-9H-carbazol-3-yl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, 1,3-dichloro-5-isocyanatobenzene, and 9-ethyl-9H-carbazol-3-aminethe title compound was obtained in 60% purity by LC/MS. MS(ESI+):m/z=532.8.

Example 157(2S,4EZ)-4-[(allyloxy)imino]-N²-(9-ethyl-9H-carbazol-3-yl)-N¹-phenyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, isocyanatobenzene, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 67% purity by LC/MS. MS(ESI+): m/z=496.4.

Example 158(2S)-N²-(9-ethyl-9H-carbazol-3-yl)-4-methylene-N¹-phenyl-1,2-pyrrolidinedicar-boxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, isocyanatobenzene, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 66%purity by LC/MS. MS(ESI+): m/z=439.2.

Example 159(2S,4EZ)-N²-(2,1,3-benzothiadiazol-4-yl)-N¹-(3,5-dichlorophenyl)-4-(methoxyimino)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1,3-dichloro-5-isocyanatobenzene, and2,1,3-benzothiadiazol-4-amine the title compound was obtained in 55%purity by LC/MS. MS(ESI+): m/z=479.6.

Example 160(2EZ)-[5-(1H-benzimidazol-2-yl)-1-(4-phenoxybenzoyl)-3-pyrrolidinyldene]ethanenitrile

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and 1,2-benzenediamine the titlecompound was obtained in 90% purity by LC/MS. MS(ESI+): m/z=421.2.

Example 161(2S,4EZ)-4-(tert-butoxyimino)-1-(2-ethoxy-1-naphthoyl)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, 2-ethoxy-1-naphthoyl chloride, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 47% purity by LC/MS. MS(ESI+): m/z=591.4.

Example 162(2S,4EZ)-1-benzoyl-N-[2-(diethylamino)ethyl]-4-(ethoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and N1,N1-diethyl-1,2-ethanediamine the titlecompound was obtained in 84% purity by LC/MS. MS(ESI+): m/z=375.2.

Example 163(2S,4EZ)-N²-(2,1,3-benzothiadiazol-4-yl)-4-[(benzyloxy)imino]-N¹-phenyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, isocyanatobenzene, and 2,1,3-benzothiadiazol-4-amine the titlecompound was obtained in 57% purity by LC/MS. MS(ESI+): m/z=487.4.

Example 164(2S,4EZ)-1-(4-cyanobenzoyl)-4-{[(3,4dichlorobenzyl)oxy]imino}-N-(1-naphthylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 1-naphthylmethylamine the titlecompound was obtained in 39% purity by LC/MS. MS(ESI+): m/z=571.6.

Example 165(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-benzoyl-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 2,1,3-benzothiadiazol-4-amine the titlecompound was obtained in 61% purity by LC/MS. MS(ESI+): m/z=502.4.

Example 166(2S,4EZ)-4-[(allyloxy)imino]-N-(2,1,3-benzothiadiazol-4-yl)-1-(diphenylacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 2,1,3-benzothiadiazol-4-amine thetitle compound was obtained in 46% purity by LC/MS. MS(ESI+): m/z=512.4.

Example 167(2S,4EZ)-4(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 75%purity by LC/MS. MS(ESI+): m/z=557.4.

Example 168(2S,4EZ)-1-benzoyl-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=469.4.

Example 169(2S,4EZ)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-(methoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 88% purity by LC/MS. MS(ESI+): m/z=437.2.

Example 170(2S,4EZ)-4-[(benzyloxy)imino]-N²-(9-ethyl-9H-carbazol-3-yl)-N¹-pentyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=540.4.

Example 171(3EZ,5S)-1-benzoyl-5-{[4-(3,4-dichlorophenyl)-1-piperazinyl]carbonyl}-3-pyrrolidinoneO-ethyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 1-(3,4-dichlorophenyl)piperazine the titlecompound was obtained in 51% purity by LC/MS. MS(ESI+): m/z=489.6.

Example 172(2S,4EZ)-4-[(allyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 48%purity by LC/MS. MS(ESI+): m/z=569.4.

Example 173(2S,4EZ)-4-{[(4-methoxybenzyl)oxy]imino}-N-(2-methoxyethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, and 2-methoxyethylamine the title compound was obtained in 52%purity by LC/MS. MS(ESI+): m/z=322.2.

Example 174(2S,4EZ)-4-[(allyloxy)imino]-N-(3,4-dimethoxybenzyl)-1-(diphenylacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 3,4-dimethoxybenzylamine the titlecompound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=528.4.

Example 175(2S,4EZ)-4-[(allyloxy)imino]-1-(4-cyanobenzoyl)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 43% purity by LC/MS. MS(ESI+): m/z=506.4.

Example 176(2S,4EZ)-4-{[(4-methoxybenzyl)oxy]imino}-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinaminethe title compound was obtained in 61% purity by LC/MS. MS(ESI+):m/z=583.4.

Example 177(2S,4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in46% purity by LC/MS. MS(ESI+): m/z=351.2.

Example 178(2S,4EZ)-N²-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-N¹-(3-methoxyphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methoxybenzene, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 100% purity by LC/MS. MS(ESI+):m/z=500.4.

Example 179(2S,4EZ)-4-(ethoxyimino)-N²-(9-ethyl-9H-carbazol-3-yl)-N¹-(3-methoxyphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methoxybenzene, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 60% purity by LC/MS. MS(ESI+): m/z=514.4.

Example 180(2S,4EZ)-1-[(4-chlorophenoxy)acetyl]-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, (4-chlorophenoxy)acetyl chloride, and 9-ethyl-9H-carbazol-3-aminethe title compound was obtained in 100% purity by LC/MS. MS(ESI+):m/z=533.4.

Example 181(2S,4EZ)-4-[(allyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-(4-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=573.4.

Example 182(2S,4EZ)-N¹-benzoyl-N²-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 59% purity by LC/MS. MS(ESI+): m/z=498.4.

Example 183(2S,4EZ)-4-[(benzyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 93%purity by LC/MS. MS(ESI+): m/z=619.6.

Example 184(2S,4EZ)-1-acetyl-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, acetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 87% purity by LC/MS. MS(ESI+): m/z=407.2.

Example 185(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 70%purity by LC/MS. MS(ESI+): m/z=545.4.

Example 186(2S,4EZ)-1-acetyl-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, acetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 69% purity by LC/MS. MS(ESI+): m/z=393.2.

Example 187(2S,4EZ)-1-(diphenylacetyl)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 77% purity by LC/MS. MS(ESI+): m/z=545.4.

Example 188(2S,4EZ)-4-[(allyloxyimino]-N¹-benzoyl-N²-(9-ethyl-9H-carbazol-3-al)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=524.4.

Example 189(2S,4EZ)-N²-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-N¹-(3-methylphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methylbenzene, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 89% purity by LC/MS. MS(ESI+): m/z=484.4.

Example 190(2S,4EZ)-4-{[(4-methoxybenzyl)oxy]imino}-N¹-pentyl-N²-(2-thienylmethyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 2-thienylmethylamine the title compoundwas obtained in 86% purity by LC/MS. MS(ESI+): m/z=473.2.

Example 191(2S,4EZ)-4-(ethoxyimino)-1-(methoxyacetyl)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and 6-quinolinamine the title compound wasobtained in 81% purity by LC/MS. MS(ESI+): m/z=371.2.

Example 192(2S,4EZ)-4-[(allyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in80% purity by LC/MS. MS(ESI+): m/z=377.2.

Example 193(2S,4EZ)-4-[(benzyloxy)imino]-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinaminethe title compound was obtained in 48% purity by LC/MS. MS(ESI+):m/z=553.4.

Example 194(2S,4EZ)-4-[(allyloxy)imino]-N-[2-(diethylamino)ethyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, and N1,N1-diethyl-1,2-ethanediamine the title compound wasobtained in 78% purity by LC/MS. MS(ESI+): m/z=283.0.

Example 195(2S,4EZ)-1-[4-(dimethylamino)butanoyl]-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)-butanoyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 42%purity by LC/MS. MS(ESI+): m/z=464.2.

Example 196(2S)-2-[(3-hydroxy-1-azetidinyl)carbonyl]-N-(3-methoxyphenyl)-4-oxo-1-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-oxoproline, 1-isocyanato-3-methoxybenzene, and3-azetidinol the title compound was obtained in 87% purity by LC/MS.MS(ESI+): m/z=334.2.

Example 197(2S,4EZ)-4-[(benzyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 65% purity by LC/MS. MS(ESI+): m/z=561.4.

Example 198(2S)-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 70%purity by LC/MS. MS(ESI+): m/z=512.4.

Example 199(2S,4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-1-(methoxyacetyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 73% purity by LC/MS. MS(ESI+): m/z=423.4.

Example 200(2S,4EZ)-N²-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-N¹-pentyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4E)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 81% purity by LC/MS. MS(ESI+): m/z=464.2.

Example 201(2S,4EZ)-4-(ethoxyimino)-N¹-pentyl-N²-[2-(1H-pyrrol-1-yl)phenyl]-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 2-(1H-pyrrol-1-yl)phenylamine the titlecompound was obtained in 83% purity by LC/MS. MS(ESI+): m/z=426.2.

Example 202(2S,4EZ)-4-[(allyloxy)imino]-N-(2-methoxyethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, and 2-methoxyethylamine the title compound was obtained in 100%purity by LC/MS. MS(ESI+): m/z=242.0.

Example 203(2S,4EZ)-4-(tert-butoxyimino)-N²-(2-methoxyethyl)-N¹-(3-methoxyphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methoxybenzene, and 2-methoxyethylamine the titlecompound was obtained in 76% purity by LC/MS. MS(ESI+): m/z=407.2.

Example 204(2S,4EZ)-4-[(allyloxy)imino]-N²-(2-methoxyethyl)-N¹-(3-methylphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methylben-zene, and 2-methoxyethylamine the titlecompound was obtained in 85% purity by LC/MS. MS(ESI+): m/z=375.2.

Example 205(2S,4EZ)-1-benzoyl-4-benzylidene-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 81% purity by LC/MS. MS(ESI+): m/z=500.4.

Example 206(2S,4EZ)-N²-benzyl-4-benzylidene-N²-methyl-N¹-(3-methylphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methylbenzene, and N-benzyl-N-methylamine the titlecompound was obtained in 68% purity by LC/MS. MS(ESI+): m/z=440.2.

Example 207(2S,4EZ)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-(4-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 99% purity by LC/MS. MS(ESI+): m/z=561.4.

Example 208(2S,4EZ)-4-(ethoxyimino)-N²-(9-ethyl-9H-carbazol-3-yl)-N¹-(3-methylphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, staring from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methylben-zene, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 80% purity by LC/MS. MS(ESI+): m/z=498.4.

Example 209(2S,4EZ)-4-(methoxyimino)-1-(phenoxyacetyl)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 6-quinolinamine the title compound wasobtained in 100% purity by LC/MS. MS(ESI+): m/z=419.2.

Example 210(2S,4EZ)-4-(tert-butoxyimino)-N-(34-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and3,4-dimethoxybenzylamine the title compound was obtained in 63% purityby LC/MS. MS(ESI+): m/z=542.4.

Example 211(2S,4EZ)-4-(tert-butoxyimino)-N-cyclopropyl-1-(phenoxyacetyl)-2pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and cyclopropylamine the title compoundwas obtained in 73% purity by LC/MS. MS(ESI+): m/z=374.2.

Example 212(2S,4EZ)-4-[(benzyloxy)imino]-N-(tert-butyl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and tert-butylamine the title compound wasobtained in 100% purity by LC/MS. MS(ESI+): m/z=424.2.

Example 213(2S,4EZ)-N-(4,6-dimethoxy-2-pyrimidinyl)-4-(ethoxyimino-1-(4-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and 4,6-dimethoxy-2-pyrimidinamine thetitle compound was obtained in 79% purity by LC/MS. MS(ESI+): m/z=506.4.

Example 214(4ZE)-4-[(allyloxy)imino]-N-(9-ethyl-9H-carbazol-3-)yl-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=511.4.

Example 215(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 66%purity by LC/MS. MS(ESI+): m/z=531.4.

Example 216(3EZ,5S)-1-[4-(dimethylamino)butanoyl]-5-(1-piperidinylcarbonyl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4(dimethylamino)butanoyl chloride, and piperidine the titlecompound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=339.2.

Example 217(2S,4EZ)-1-acetoacetyl-N-(9-ethyl-9H-carbazol-3-yl)4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2,4-oxetanedione, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 42% purity by LC/MS. MS(ESI+): m/z=435.2.

Example 218(2S,4EZ)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinaminethe title compound was obtained in 57% purity by LC/MS. MS(ESI+):m/z=477.2.

Example 219(2S,4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-4-{[(4-methoxybenzyl)oxy]imino}-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 57%purity by LC/MS. MS(ESI+): m/z=649.4.

Example 220(2S,4EZ)-N²-allyl-N¹-benzoyl-4-(methoxyimino)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and allylamine the title compound was obtainedin 49% purity by LC/MS. MS(ESI+): m/z=345.0.

Example 221(2S,4EZ)-4-[(benzyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-(methoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 46% purity by LC/MS. MS(ESI+): m/z=499.2.

Example 222(2S,4EZ)-N¹-(3,5-dichlorophenyl)-N²-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1,3-dichloro-5-isocyanatobenzene, and 9-ethyl-9H-carbazol-3-aminethe title compound was obtained in 42% purity by LC/MS. MS(ESI+):m/z=538.2.

Example 223(2S,4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1-(4-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 43% purity by LC/MS. MS(ESI+): m/z=547.2.

Example 224(2S,4EZ)-N¹-(3,5-dichlorophenyl)-4-(ethoxyimino)-N²-(9-ethyl-9H-carbazol-3-yl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 1,3-dichloro-5-isocyanatobenzene, and 9-ethyl-9H-carbazol-3-aminethe title compound was obtained in 43% purity by LC/MS. MS(ESI+):m/z=552.6.

Example 225(3EZ,5S)-5-{[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]carbonyl}-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-3-pyrrolidinoneO-(tert-butyl)oxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and1-(1,3-benzodioxol-5-ylmethyl)piperazine the title compound was obtainedin 59% purity by LC/MS. MS(ESI+): m/z=595.4.

Example 226(2S,4EZ)-4-benzylidene-N-(9-ethyl-9H-carbazol-3-yl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 47%purity by LC/MS. MS(ESI+): m/z=588.4.

Example 227(2S,4EZ)-4-[(allyloxy)imino]-1-benzoyl-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 6-quinolinamine the title compound wasobtained in 83% purity by LC/MS. MS(ESI+): m/z=415.2.

Example 228(2S,4EZ)-4-[(allyloxy)imino]-1-(methoxyacetyl)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and 6-quinolinamine the title compound wasobtained in 71% purity by LC/MS. MS(ESI+): m/z=383.0.

Example 229(2S,4EZ)-4-[(allyloxy)imino]-N-ethyl-9H-carbazol-3-yl)-1-(methoxyacetyl)2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=449.2.

Example 230(2S,4EZ)-4-[(allyloxy)imino]-1-(2-ethoxy-1-naphthoyl)-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-₄-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-ethoxy-1-naphthoyl chlo-ride, and 9-ethyl-9H-carbazol-3-aminethe title compound was obtained in 60% purity by LC/MS. MS(ESI+):m/z=575.4.

Example 231(2S,4EZ)-4-[(allyloxy)imino]-1-[(4-chlorophenoxy)acetyl]-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, (4-chlorophenoxy)acetyl chloride, and 9-ethyl-9H-carbazol-3-aminethe title compound was obtained in 78% purity by LC/MS. MS(ESI+):m/z=545.4.

Example 232(2S,4EZ)-4-[(allyloxy)imino]-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 51%purity by LC/MS. MS(ESI+): m/z=557.2.

Example 233(2S,4EZ)-4-[(allyloxy)imino]-1-(diphenylacetyl)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 43% purity by LC/MS. MS(ESI+): m/z=571.2.

Example 234(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(tert-butyl)-4-(chloromethylene)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbo-nyl chloride, and tert-butylamine thetitle compound was obtained in 80% purity by LC/MS. MS(ESI+): m/z=397.6.

Example 235 tert-butyl3-[({4-methylene-1-[(pentylamino)carbonyl]-2-pyrrolidinyl}carbonyl)amino]-1-azetidinecarboxylate

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, 1-isocyanatopentane, andtert-butyl 3-amino-1-azetidinecarboxylate the title compound wasobtained in 75% purity by LC/MS. MS(ESI+): m/z=395.2.

Example 236(3EZ,5S)-1-acetyl-5-[(4-acetyl-1-piperazinyl)carbonyl]-3-pyrrolidinoneO-(3,4-dichlorobenzyl)oxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, acetyl chloride, and 1-acetylpiperazine the title compound wasobtained in 85% purity by LC/MS. MS(ESI+): m/z=455.2.

Example 237(2S,4EZ)-N²-benzyl-4-(methoxyimino)-N¹-pentyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and benzylamine the title compound wasobtained in 100% purity by LC/MS. MS(ESI+): m/z=361.0.

Example 238(2S,4EZ)-1-acetyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(1-naphthylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, acetyl chloride, and 1-naphthylmethylamine the title compound wasobtained in 60% purity by LC/MS. MS(ESI+): m/z=484.2.

Example 239(2S,4EZ)-4-(tert-butoxyimino)-N-cyclopropyl-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and cyclopropylaminethe title compound was obtained in 75% purity by LC/MS. MS(ESI+):m/z=432.2.

Example 240(2S,4EZ)-4-{[(4-methoxybenzyl)oxy]imino}-1-(4-phenoxybenzoyl)-N-[2-(1H-pyrrol-1-yl)phenyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and 2-(1H-pyrrol-1-yl)phenylamine thetitle compound was obtained in 55% purity by LC/MS. MS(ESI+): m/z=601.4.

Example 241(2S)-N-(1,3-benzodioxol-5-ylmethyl)-4-oxo-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-oxoproline, and1,3-benzodioxol-5-ylmethylamine the title compound was obtai-ned in 71%purity by LC/MS. MS(ESI+): m/z=263.0.

Example 242(2S,4EZ)-N-(1,3-benzodioxol-5-ylmethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbo-nyl chloride, and1,3-benzodioxol-5-ylmethylamine the title compound was obtained in 63%purity by LC/MS. MS(ESI+): m/z=475.6.

Example 243(2S,4EZ)-N-(3,4-dimethoxybenzyl)-4-(ethoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and3,4-dimethoxybenzylamine the title compound was obtained in 41% purityby LC/MS. MS(ESI+): m/z=514.2.

Example 244(2S)-2-[(3-hydroxy-1-azetidinyl)carbonyl]-N-(3-methylphenyl)-4-oxo-1-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-oxoproline, 1-isocyanato-3-methylbenzene, and3-azetidinol the title compound was obtained in 73% purity by LC/MS.MS(ESI+): m/z=318.0.

Example 245(2S,4EZ)-4-[(benzyloxy)imino]-N-[(2RS)-2-hydroxy-2-phenethyl]-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and(1RS)-2-amino-1-phenylethanol the title compound was obtained in 55%purity by LC/MS. MS(ESI+): m/z=546.2.

Example 246(2S,4EZ)-4-[(allyloxy)imino]-N²-(3,4-dimethoxybenzyl)-N¹-(3-methoxyphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methoxybenzene, and 3,4-dimethoxybenzylamine thetitle compound was obtained in 97% purity by LC/MS. MS(ESI+): m/z=483.2.

Example 247(2S,4EZ)-4-[(allyloxy)imino]-1-(4-cyanobenzoyl)-N-(2-methoxyethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 2-methoxyethylamine the titlecompound was obtained in 44% purity by LC/MS. MS(ESI+): m/z=371.0.

Example 248(2S,4EZ)-N-benzyl-1-(methoxyacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidine-carboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and benzylamine the title compound wasobtained in 49% purity by LC/MS. MS(ESI+): m/z=426.2.

Example 249(2S,4EZ)-1-benzoyl-4-(chloromethylene)-N-(2-furylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 2-furylmethylamine the title compound wasobtained in 73% purity by LC/MS. MS(ESI+): m/z=345.6.

Example 250(2S)-1-acetyl-4-methylene-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, acetyl chloride, and6-quinolinamine the title compound was obtained in 87% purity by LC/MS.MS(ESI+): m/z=296.0.

Example 251(2S,4EZ)-1-acetyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(2-furylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, acetyl chloride, and 2-furylmethylamine the title compound wasobtained in 199% purity by LC/MS. MS(ESI+): m/z=424.6.

Example 252(2S)-N¹-(3,5-dichlorophenyl)-4-methylene-N²-(6-quinolinyl)-1,2-pyrrolidinedicar-boxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxy-carbonyl)-4-methyleneproline,1,3-dichloro-5-isocyanatobenzene, and 6-quinolinamine the title compoundwas obtained in 65% purity by LC/MS. MS(ESI+): m/z=441.0.

Example 253(3EZ,5S)-1-(diphenylacetyl)-5-(1-piperidinylcarbonyl)-3-pyrrolidinoneO-(4-methoxybenzyl)oxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and piperidine the title compound wasobtained in 87% purity by LC/MS. MS(ESI+): m/z=526.4.

Example 254(2S,4EZ)-4-(chloromethylene)-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyrrolidine-carboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 1-naphthylmethylamine the titlecompound was obtained in 75% purity by LC/MS. MS(ESI+): m/z=435.6.

Example 255(2S,4EZ)-4-[(allyloxy)imino]-N-benzoyl-2-(4-morpholinylcarbonyl)-1-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and morpholine the title compound was obtainedin 46% purity by LC/MS. MS(ESI+): m/z=401.2.

Example 256(2S,4EZ)-N¹-benzoyl-4-(chloromethylene)-N²-cyclopropyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and cyclopropylamine the title compound wasobtained in 76% purity by LC/MS. MS(ESI+): m/z=348.6.

Example 257(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(methoxyacetyl)-N-(1-naphthylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and 1-naphthylmethylamine the titlecompound was obtained in 91% purity by LC/MS. MS(ESI+): m/z=514.8.

Example 258(2S,4EZ)-1-benzoyl-N-benzyl-4-(chloromethylene)-N-methyl-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and N-benzyl-N-methylamine the title compoundwas obtained in 62% purity by LC/MS. MS(ESI+): m/z=369.4.

Example 259(2S)-N²-(2-furylmethyl)-N¹-(3-methoxyphenyl-4-methylene-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,1-isocyanato-3-methoxybenzene, and 2-furylmethylamine the title compoundwas obtained in 95% purity by LC/MS. MS(ESI+): m/z=356.0.

Example 260(3EZ,5S)-5-[(4-benzhydryl-1-piperazinyl)carbonyl]-1-(phenoxyacetyl)-3-pyrrolidinoneO-ethyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 1-benzhydrylpiperazine the titlecompound was obtained in 67% purity by LC/MS. MS(ESI+): m/z=541.2.

Example 261 (3EZ,5S)-1-benzoyl-5-(4-morpholinylcarbonyl)-3-pyrrolidinoneO-(3,4-dichlorobenzyl)-oxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, benzoyl chloride, and morpholine the title compound was obtainedin 69% purity by LC/MS. MS(ESI+): m/z=476.2.

Example 262(2S)-N¹-(3-methoxyphenyl)-4-methylene-N²-(1-naphthylmethyl-1,2-pyrrolidine-dicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,1-isocyanato-3-methoxybenzene, and 1-naphthylmethyl-amine the titlecompound was obtained in 55% purity by LC/MS. MS(ESI+): m/z=416.3.

Example 263N²-(2-methoxyethyl)-4-methylene-N¹-(3-methylphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,1-isocyanato-3-methylbenzene, and 2-methoxyethylamine the title compoundwas obtained in 85% purity by LC/MS. MS(ESI+): m/z=318.0.

Example 264(2S,4EZ)-N-allyl-4-{[(4-methoxybenzyl)oxy]imino}-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and allylamine the title compound wasobtained in 72% purity by LC/MS.

MS(ESI+): m/z=438.2.

Example 265(2S,4EZ)-1-benzoyl-4-(cyanomethylene)-N-(1-naphthylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 1-naphthylmethylamine the title compound wasobtained in 43% purity by LC/MS. MS(ESI+): m/z=396.0.

Example 266(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinaminethe title compound was obtained in 70% purity by LC/MS. MS(ESI+):m/z=621.2.

Example 267(2S,4EZ)-N-[2-(diethylamino)ethyl]-1-[4-(dimethylamino)butanoyl]-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)butanoyl chloride, andN1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 100%purity by LC/MS. MS(ESI+): m/z=476.2.

Example 268(2S,4EZ)-4-[(allyloxy)imino]-1-[4-(dimethylamino)butanoyl]-N-(1-naphthylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)buta-noyl chloride, and 1-naphthylmethylamine thetitle compound was obtained in 85% purity by LC/MS. MS(ESI+): m/z=437.2.

Example 269(2S,4EZ)-N-[2-(diethylamino)ethyl]-4-(ethoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, and N1,N1-diethyl-1,2-ethanediamine the title compound wasobtained in 70% purity by LC/MS. MS(ESI+): m/z=271.0.

Example 270(2S)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinamine thetitle compound was obtained in 48% purity by LC/MS. (ESI+): m/z=446.2.

Example 271(2S,4EZ)-1-acryloyl-N-allyl-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, acryloyl chloride, and allylamine the title compound was obtainedin 81% purity by LC/MS. MS(ESI+): m/z=252.0.

Example 273 tert-butyl3-({[(2S,4EZ)-1-acetyl-4-benzylidenepyrrolidinyl]carbonyl}amino)-1-azetidinecarboxylate

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, acetyl chloride, and tert-butyl 3-amino-1-azetidinecarboxylate thetitle compound was obtained in 81% purity by LC/MS. MS(ESI+): m/z=400.2.

Example 273(2S,4EZ)-4-[(allyloxy)imino]-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinaminethe title compound was obtained in 67% purity by LC/MS. MS(ESI+):m/z=503.2.

Example 274(2S,4EZ)-4-(ethoxyimino)-N-(1-naphthylmethyl-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 1-naphthylmethylamine the titlecompound was obtained in 85% purity by LC/MS. MS(ESI+): m/z=446.3.

Example 275(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 96.4%purity by HPLC. MS(ESI+): m/z=472.

Example 276(2S,4EZ)-1-([1,1′-biphenyl]-3-ylcarbonyl)-N-(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-3-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 72%purity by HPLC. MS(ESI+): m/z=458.

Example 277(2S,4EZ)-1-(4-benzoylbenzoyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-benzoylbenzoic acid, and (1RS)-2-amino-1-phenylethanol, thetitle compound was obtained in 93% purity by HPLC. MS(ESI+): m/z=486.

Example 278(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-(3-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 3-phenoxybenzoic acid, and (1RS)-2-amino-1-phenylethanol, thetitle compound was obtained in 94% purity by HPLC. MS(ESI+): m/z=474.

Example 279(2S,4EZ)-N-(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)1-(2-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2-phenoxybenzoic acid, and (1RS)-2-amino-1-phenylethanol, thetitle compound was obtained in 92% purity by HPLC. MS(ESI+): m/z=474.

Example 280(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1S)-2-amino-1-phenylethanol, the title compound was obtained in 98%purity HPLC. MS(ESI+): m/z=472.

Example 281(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1R)-2-amino-1-phenylethanol, the title compound was obtained in 84%purity by HPLC. MS(ESI+): m/z=472.

Example 282(2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2-aminoethanol,the title compound was obtained in 75% purity by HPLC. MS(ESI+):m/z=396.

Example 283(2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-N-methyl-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and2-(methylamino)ethanol, the title compound was obtained in 78% purity byHPLC. MS(ESI+): m/z=410.

Example 284(2S,4EZ)-1-([1,1′-biphenyl]-4sulfonyl)-N-(1S,2S,3R,4R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]4-sulfonyl chloride, and[(1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the titlecompound was obtained in 79% purity by HPLC. MS(ESI+): m/z=498.

Example 285(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(trans-4-hydroxycyclohexyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, andtrans-4-aminocyclohexanol, the title compound was obtained in 62% purityby HPLC. MS(ESI+): m/z=436.

Example 286(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and[(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in65% purity by HPLC. MS(ESI+): m/z=450.

Example 287(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, staring from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained in68% purity by HPLC. MS(ESI+): m/z=488.

Example 288(2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and(2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained in76% purity by HPLC. MS(ESI+): m/z=489.

Example 289(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained in78% purity by HPLC. MS(ESI+): m/z=524.

Example 290(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 63% purity by HPLC. MS (ESI+): m/z=474.4.

Example 291(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4sulfonyl chloride, and4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 72% purity by HPLC. MS(ESI+): m/z=510.

Example 292(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1-hydroxycyclohexyl)methyl]-4-(methoxyimino-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and1-(aminomethyl)cyclohexanol, the title compound was obtained in 65%purity by HPLC. MS(ESI+): m/z=450.

Example 293(2S,4EZ)-N-(1-hydroxycyclohexyl)methyl]-4-(methoxyimino)-1-[4-(3-pyridin)benzoyl]-2pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and 1-(aminomethyl)cyclohexanol, thetitle compound was obtained in 69% purity by HPLC. MS(ESI+): m/z=451.

Example 294(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1-hydroxycyclohexyl)methyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]4-sulfonyl chloride, and1-(aminomethyl)cyclohexanol, the title compound was obtained in 66%purity by HPLC. MS(ESI+): m/z=486.

Example 295(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]4-carbonyl chloride, and4-(1RS)-2-amino-1-hydroxyethyl-1,2-benzenediol, the title compound wasobtained in 66% purity by HPLC. MS(ESI+): m/z=490.

Example 296(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, and (1S)-2-amino-1-phenylethanol, thetitle compound was obtained in 65% purity by HPLC. MS(ESI+): m/z=459.

Example 297(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and (1S)-2-amino-1-phenylethanol, thetitle compound was obtained in 73% purity by HPLC. MS(ESI+): m/z=459.

Example 298(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(2-pyridinyl)benzoic acid, and (1S)-2-amino-1-phenylethanol, thetitle compound was obtained in 69% purity by HPLC. MS(ESI+): m/z=459.

Example 299(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(2RS)-3-amino-1,2-propanediol, the title compound was obtained in 73%purity by HPLC. MS(ESI+): m/z=412.

Example 300(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2,3-dihdroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]4-sulfonyl chloride, and(2RS)-3-amino-1,2-propanediol, the title compound was obtained in 64%purity by HPLC. MS(ESI+): m/z=448.

Example 301(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-27pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound wasobtained in 81% purity by HPLC. MS(ESI+): m/z=518.

Example 302(2S,4EZ)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and(2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound wasobtained in 63% purity by HPLC. MS(ESI+): m/z=519.

Example 303(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound wasobtained in 69% purity by HPLC. MS(ESI+): m/z=554.

Example 304(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxypropyl-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and (2RS)-1-amino-2-propanol,the title compound was obtained in 82% purity by HPLC. MS(ESI+):m/z=396.

Example 305(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and (2RS)-1-amino-2-propanol,the title compound was obtained in 75% purity by HPLC. MS(ESI+):m/z=432.

Example 306(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(2-naphthyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(1RS)-2-amino-1-(2-naphthyl)ethanol, the title compound was obtained in77% purity by HPLC. MS(ESI+): m/z=544.

Example 307(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-L(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4E2)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was obtainedin 84% purity by HPLC. MS(ESI+): m/z=503.

Example 308(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenylethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, and(1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was obtainedin 89% purity by HPLC. MS(ESI+): m/z=504.

Example 309(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and(1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was obtainedin 72% purity by HPLC. MS(ESI+): m/z=504.

Example 310(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(2-pyridinyl)benzoic acid, and(1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was obtainedin 63% purity by HPLC. MS(ESI+): m/z=504.

Example 311(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was obtainedin 79% purity by HPLC. MS(ESI+): m/z=539.

Example 312(2S,4E2)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, andN-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl)acetamide, the titlecompound was obtained in 79% purity by HPLC. MS(ESI+): m/z=545.

Example 313(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, andN-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl) acetamide, the titlecompound was obtained in 62% purity by HPLC. MS(ESI+): m/z=546.

Example 314(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, andN-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl) acetamide, the titlecompound was obtained in 66% purity by HPLC. MS(ESI+): m/z=546.

Example 315(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, andN-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl) acetamide, the titlecompound was obtained in 62% purity by HPLC. MS(ESI+): m/z=581.

Example 316(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1R)-2-amino-1-phenylethanol, the title compound was obtained in 84%purity by HPLC. MS(ESI+): m/z=458.

Example 317(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, and (1R)-2-amino-1-phenylethanol, thetitle compound was obtained in 66% purity by HPLC. MS(ESI+): m/z=459.

Example 318(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and (1R)-2-amino-1-phenylethanol, thetitle compound was obtained in 76% purity by HPLC. MS(ESI+): m/z=459.

Example 319(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(2-pyridinyl)benzoic acid, and (1R)-2-amino-1-phenylethanol, thetitle compound was obtained in 65% purity by HPLC. MS(ESI+): m/z=459.

Example 320(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(1R)-2-amino-1-phenylethanol, the title compound was obtained in 87%purity by HPLC. MS(ESI+): m/z=494.

Example 321(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(3-hydroxypropyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 3-amino-1-propanol, thetitle compound was obtained in 81% purity by HPLC. MS(ESI+): m/z=395.

Example 322(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-(3-hydroxypropyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]4-sulfonyl chloride, and 3amino-1-propanol, thetitle compound was obtained in 64% purity by HPLC. MS(ESI+): m/z=432.

Example 323(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxyphenyl-1-piperidinyl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 4-phenyl-4-piperidinol,the title compound was obtained in 74% purity by HPLC. MS(ESI+):m/z=498.

Example 324(3EZ,5S)-5-[(4-hydroxy-4-phenyl-1-piperdinyl]carbonyl]-1-[4-(4-pyridinyl)benzoyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, and 4-phenyl-4-piperidinol, the titlecompound was obtained in 78% purity by HPLC. MS(ESI+): m/z=499.

Example 325(3EZ,5S)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl-1-[4-(3-pyridinyl)benzoyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and 4-phenyl-4-piperidinol, the titlecompound was obtained in 79% purity by HPLC. MS(ESI+): m/z=499.

Example 326(3EZ,5s)-1-([1,1′-biphenyl]-4-ylsulfonyl)-5-[(4hydroxy-4-phenyl-1-piperidinyl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and 4-phenyl-4-piperidinol,the title compound was obtained in 84% purity by HPLC. MS(ESI+):m/z=534.

Example 327(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N[(1S,2EZ)-2-hydroxycyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride,and,(1S,2S)-2-aminocyclohexanol, the title compound was obtained in 84%purity by HPLC. MS(ESI+): m/z=436.

Example 328(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(1S,2S)-2-aminocyclohexanol, the title compound was obtained in 61%purity by HPLC. MS(ESI+): m/z=472.

Example 329(2S,4EZ)-N-benzyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1-biphenyl]-4-carbonyl chloride, and 2-(benzylamino)ethanol,the title compound was obtained in 74% purity by HPLC. MS(ESI+):m/z=472.

Example 330 (2S,4EZ)-N-b[1-N-(2hydroxyethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and 2-(benzylamino)ethanol, the titlecompound was obtained in 82% purity by HPLC. MS(ESI+): m/z=473.

Example 331(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and (3RS)-3-piperidinol, thetitle compound was obtained in 78% purity by HPLC. MS(ESI+): m/z=422.

Example 332(3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-1-[4-(4-pyridinyl)benzol]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, and (3RS)-3-piperidinol, the titlecompound was obtained in 91% purity by HPLC. MS(ESI+): m/z=423.

Example 333(3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-1-4-(3-pyridinyl)benzoyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and (3RS)-3-piperidinol, the titlecompound was obtained in 84% purity by HPLC. MS(ESI+): m/z=423.

Example 334(3EZ,5S)-1-([1,1′-biphenyl]-4-ylsulfonyl)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and (3RS)-3-piperidinol, thetitle compound was obtained in 79% purity by HPLC. MS(ESI+): m/z=458.

Example 335(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound wasobtained in 88% purity by HPLC. MS(ESI+): m/z=488.

Example 336(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-1-(4-pyridinyl)benzoyl]-2pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, and(1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound wasobtained in 64% purity by HPLC. MS(ESI+): m/z=489.

Example 337(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and(1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound wasobtained in 93% purity by HPLC. MS(ESI+): m/z=489.

Example 338(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound wasobtained in 82% purity by HPLC. MS(ESI+): m/z=524.

Example 339(2S,4EZ)-N-(2-anilinoethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, andN²-phenyl-1,2-ethanediamine, the title compound was obtained in 93%purity by HPLC. MS(ESI+): m/z=457.

Example 340(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, and N¹-phenyl-1,2-ethanediamine, thetitle compound was obtained in 85% purity by HPLC. MS(ESI+): m/z=458.

Example 341(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and N¹-phenyl-1,2-ethanediamine, thetitle compound was obtained in 85% purity by HPLC. MS(ESI+): m/Z=458.

Example 342(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(2-pyridin)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(2-pyridinyl)benzoic acid, and N¹-phenyl-1,2-ethanediamine, thetitle compound was obtained in 67% purity by HPLC. MS(ESI+): m/z=458.

Example 343(2S,4EZ)-N-(2-anilinoethyl)-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]4-sulfonyl chloride, andN¹-phenyl-1,2-ethanediamine, the title compound was obtained in 73%purity by HPLC. MS(ESI+): m/z=493.

Example 344(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 4-piperidinol, the titlecompound was obtained in 86% purity by HPLC. MS(ESI+): m/z=422.

Example 345(3EZ,56)-1-([1,1′-biphenyl]-4-ylsulfonyl-5-[(4-hydroxy-1-piperidinyl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]4-sulfonyl chloride, and 4-piperidinol, the titlecompound was obtained in 68% purity by HPLC. MS(ESI+): m/z=458.

Example 346(2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylsulfonyl)-4(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(1R,2S,3,R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the titlecompound was obtained in 79% purity by HPLC. MS(ESI+): m/z=509.

Example 347(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]carbonyl chloride, and 3-aminopropanamide, thetitle compound was obtained in 71% purity by HPLC. MS(ESI+): m/z=409.

Example 348(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the titlecompound was obtained in 83% purity by HPLC. MS(ESI+): m/z=509.

Example 349(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl-N-(4-hydroxybutyl-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 4-amino-1-butanol, thetitle compound was obtained in 68% purity by HPLC. MS(ESI+): m/z=410.

Example 350(2S,4EZ)-([1,1′-biphenyl]-4-ylsulfonyl)-N-(4-hydroxybutyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and 4-amino-1-butanol, thetitle compound was obtained in 78% purity by HPLC. MS(ESI+): m/z=446.

Example 351(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4sulfonyl chloride, and[(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in40% purity by HPLC. MS(ESI+): m/z=486.

Example 352(2S,4EZ)-1-([1,1′-biphenyl]-4ylsulfonyl)-N-[(1R,2S,3R,4S)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyly]4-sulfonyl chloride, and[(1S,2R,3S,4R)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the titlecompound was obtained in 58% purity by HPLC. MS(ESI+): m/z=498.

Example 353(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1R,2S)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and[(1S,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in41% purity by HPLC. MS(ESI+): m/z=486.

Example 354 (2S,4E and4Z)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino-1-(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compounds were obtained as amixture of E/Z-isomers of the oxime functionality. Separation of theisomers by flash chromatography yielded(2S,4E)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamidein 98.9% purity and(2S,4Z)-N-[(2RS)-2-hydroxy-2-phenylethyl]4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamidein 99.9% purity by HPLC. MS(ESI+): m/z=472.

Example 355 (2S,4E and4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1S)-2-amino-1-phenylethanol, the title compounds were obtained as amixture of E/Z-isomers of the oxime functionality. Separation of theisomers by flash chromatography yielded(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamidein 98.9% parity and(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamidein 99.8% purity by HPLC. MS(ESI+): m/z=472.

Example 356 (2S,4E and4Z)-N-[(2R)-2-hydroxy-2-phenylethyl-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1R)-2-amino-1-phenylethanol, the title compounds were obtained as amixture of E/Z-isomers of the oxime functionality. Separation of theisomers by flash chromatography yielded(2S,4E)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamidein 99.7% purity and(2S,4Z)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamidein 99.7% purity by HPLC. MS(ESI+): m/z=472.

Example 357(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(1R,2S)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]4-carbonyl chloride, and[(1S,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in63% purity by HPLC. MS(ESI+): m/z=450.

Example 358(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]4-carbonyl chloride, and 2-amino-1,3-propanediol,the title compound was obtained in 61% purity by HPLC. MS(ESI+):m/z=412.

Example 359(2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]4-carbonyl chloride, and(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the titlecompound was obtained in 68% purity by HPLC. MS(ESI+): m/z=473.

Example 360(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the titlecompound was obtained in 78% purity by HPLC. MS(ESI+): m/z=473.

Example 361(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1S)-2-amino-1-phenylethanol, the title compound was obtained in 87%purity by HPLC. MS(ESI+): m/z=458.

Example 362(2RS)-3-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)-2-hydroxypropanoicacid

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(2RS)-3-amino-2-hydroxypropanoic acid, the title compound was obtainedin 44% purity by HPLC. MS(ESI+): m/z=426.

Example 363(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-([1,1′-biphenyl]-4-ylcarbonyl-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1S,2R)-2-aminocyclohexanecarboxamide, the title compound was obtainedin 89% purity by HPLC. MS(ESI+): m/z=463.

Example 364(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1RS)-2-hydroxy-1-methylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and (2RS)-2-amino-1-propanol,the title compound was obtained in 81% purity by HPLC. MS(ESI+):m/z=396.

Example 365(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, the title compoundwas obtained in 70% purity by HPLC. MS(ESI+): m/z=533.

Example 3664-({[(2S,4EZ)-1-([1,1′-biphenyl]-ylcarbonyl)-4(methoxyimino)pyrolidinyl]carbonyl}amino)butanoicacid

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 4-aminobutanoic acid, thetitle compound was obtained in 57% purity by HPLC. MS(ESI+): m/z=424.

Example 367(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and(1S)-2-amino-1-phenylethanol, the title compound was obtained in 90%purity by HPLC. MS(ESI+): m/z=488.

Example 368(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(2-naphthyl)ethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-ylcarbonyl-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-(2-naphthyl)ethanol, the title compound was obtained in67% purity by HPLC. MS(ESI+): m/z=538.

Example 369(2S,4EZ)-N-[(1RS)-2-hydroxy-1-methylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(2RS)-2-amino-1-propanol, the title compound was obtained in 88% purityby HPLC. MS(ESI+): m/z=410.

Example 370(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, the title compoundwas obtained in 74% purity by HPLC. MS(ESI+): m/z=547.

Example 371(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and(1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, the title compoundwas obtained in 61% purity by HPLC. MS(ESI+): m/z=563.

Example 372(3EZ,5S)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-1-[(2′-methyl]-1,1′-biphenyl]-4-ylcarbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 4-piperidinol, thetitle compound was obtained in 86% purity by HPLC. MS(ESI+): m/z=436.

Example 373(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-4-(methoxyimino)-1-(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the titlecompound was obtained in 55% purity by HPLC. MS(ESI+): m/z=487.

Example 374(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 82%purity by HPLC. MS(ESI+): m/z=488.

Example 375(2S,4EZ)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(2RS)-1-amino-2-propanol, the title compound was obtained in 90% purityby HPLC. MS(ESI+): m/z=410.

Example 376(2S,4EZ)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]4-carboxylic acid, and(2RS)-3-amino-1,2-propanediol, the title compound was obtained in 67%purity by HPLC. MS(ESI+): m/z=426.

Example 377(2S,4EZ)-N-(3-hydroxypropyl)-4-methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2-methyl[1,1′-biphenyl]-4-carboxylic acid, and 3-amino-1-propanol,the title compound was obtained in 90% purity by HPLC. MS (ESI+):m/z=410.

Example 378(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-aminoacetamide, thetitle compound was obtained in 82% purity by HPLC. MS(ESI+): m/z=395.

Example 379(2S,4EZ)-N-(2-amino-2-oxoethyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2-aminoacetamide,the title compound was obtained in 92% purity by HPLC. MS(ESI+):m/z=409.

Example 380(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 88% purity by HPLC. MS(ESI+): m/z=504.

Example 381(2S,4E)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2R,3S,4R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and[(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the titlecompound was obtained in 64% purity by HPLC. MS(ESI+): m/z=462.

Example 382(2S,4EZ)-N-[(1R,2S,3R,4S)-3-hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and[(1S,2R,3S,4R)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the titlecompound was obtained in 56% purity by HPLC. MS(ESI+): m/z=492.

Example 383(2S,4EZ)-N-(trans-4-hydroxycyclohexyl)-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4carboxylic acid, andtrans-4-aminocyclohexanol, the title compound was obtained in 61% purityby HPLC. MS(ESI+): m/z=466.

Example 384(2S,4EZ)-N-[(1R,2R)-2-hydroxymethyl)cyclohexyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and[(1R,2R)-2-aminocyclobexyl]methanol, the title compound was obtained in68% purity by HPLC. MS(ESI+): m/z=480.

Example 385(2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained in80% purity by HPLC. MS(ESI+): m/z=502.

Example 386(2-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenylethyl]-4-methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 76% purity by HPLC. MS(ESI+): m/z=488.

Example 387(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethylphenol, the title compound was obtainedin 90% purity by HPLC. MS(ESI+): m/z=504.

Example 388(2S,4EZ)-N-[(2R)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-1-[(2′-methyl]-[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethyl]-2-methoxyphenol, the title compound wasobtained in 67% purity by HPLC. MS(ESI+): m/z=518.

Example 389(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl-1-[(2-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethyl]-2-methoxyphenol, the title compound wasobtained in 87% purity by HPLC. MS(ESI+): m/z=534.

Example 390(2S,4EZ)-N-[(2RS)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-1-[2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethyl]-1,2-benzenediol, the title compound wasobtained in 69% purity by HPLC. MS(ESI+): m/z=520.

Example 391(2R,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2R,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 90%purity by HPLC. MS(ESI+): m/z=456.

Example 392(2R,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2R,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 94%purity by HPLC. MS(ESI+): m/z=472.

Example 393(2S,4EZ)-1-[(2′-cyano[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-cyano[1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 86%purity by HPLC. MS(ESI+): m/z=483.

Example 394(2S,4EZ)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 3′,4′-dichloro[1,1-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 89%purity by HPLC. MS(ESI+): m/z=527.

Example 395(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 95%purity by HPLC. MS(ESI+): m/z=486.

Example 396(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]4carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 83%purity by HPLC. MS(ESI+): m/z=486.

Example 397 (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenylethyl-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 70% purity by HPLC. MS(ESI+): m/z=488.

Example 398(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′-cyano[1,1′-biphenyl]-4-ylcarbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-cyano[1,1′-biphenyl]4-carboxylic acid, and3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 86% purity by HPLC. MS(ESI+): m/z=499.

Example 399(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 3′,4′-dichloro[1,1-biphenyl]-4-carboxylic acid, and3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 91% purity by HPLC. MS(ESI+): m/z=543.

Example 400 (2S,4EZ)-N-[(2RS)-2hydroxy-2-(3-hydroxyphenyl)ethyl]-4(methoxyimino)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 87% purity by HPLC. MS(ESI+): m/z=502.

Example 401(2S,4EZ)-N-[(2S)-2-hydroxy-2-(3-hydroxyphenylethyl]-4(methoxyimino)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 91% purity by HPLC. MS(ESI+): m/z=502.

Example 402(2S,4EZ)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 3′,4′-dichloro[1,1′-biphenyl]-4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 86% purity by HPLC. MS(ESI+): m/z=543.

Example 403(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 89% purity by HPLC. MS(ESI+): m/z=502.

Example 404(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 90% purity by HPLC. MS(ESI+): m/z=502.

Example 405(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and(2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound wasobtained in 87% purity by HPLC. MS(ESI+): m/z=546.

Example 406(2S,4EZ)-1-(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and(2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound wasobtained in 77% purity by HPLC. MS(ESI+): m/z=546.

Example 407(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]4-carboxylic acid, and2-aminoacetamide, the title compound was obtained in 88% purity by HPLC.MS(ESI+): m/z=423.

Example 408(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and2-aminoacetamide, the title compound was obtained in 85% purity by HPLC.MS(ESI+): m/z=423.

Example 409(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and3-aminopropionamide, the title compound was obtained in 87% purity byHPLC. MS(ESI+): m/z=437.

Example 410(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]4-carboxylic acid, and3-aminopropionamide, the title compound was obtained in 87% purity byHPLC. MS(ESI+): m/z=437.

Example 411(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and2-amino-1,3-propanediol, the title compound was obtained in 70% purityby HPLC. MS(ESI+): m/z=440.

Example 412(2S,4EZ)-1-[(2′,3′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and2-amino-1,3-propanediol, the title compound was obtained in 68% purityby HPLC. MS(ESI+): m/z=440.

Example 413(2,4EZ)-1-[(2′-cyano[1,1′-biphenyl]-4-yl)carbonyl]-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-cyano[1,1′-biphenyl]-4-carboxylic acid, and[(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in78% purity by HPLC. MS(ESI+): n/z=475.

Example 414(3EZ,5S)-5-(3,4-dihydro-2(1H)-isoquinolinylcarbonyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and1,2,3,4-tetrahydroisoquinoline, the title compound was obtained in 77%purity by HPLC. MS(ESI+): m/z=482.

Example 415(2S,4EZ)-N-[(1R)-2-hydroxy-1-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(2R)-2-amino-2-phenylethanol, the title compound was obtained in 91%purity by HPLC. MS (ESI+): m/z=472.

Example 416(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and4-(2-aminoethyl)phenol, the title compound was obtained in 87% purity byHPLC. MS(ESI+): m/z=486.

Example 417(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]4-yl)carbonyl]-N-[2-(4-hydroxyphenyl)ethyl-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and4-(2-aminoethyl)phenol, the title compound was obtained in 83% purity byHPLC. MS(ESI+): m/z 486.

Example 418(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyphenyl)ethyl-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and3-(2-aminoethyl)phenol, the title compound was obtained in 81% purity byHPLC. MS(ESI+): m/z=486.

Example 419(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1-biphenyl]-4carboxylic acid, and3-(2-aminoethyl)phenol, the title compound was obtained in 89% purity byHPLC. MS(ESI+): m/z=486.

Example 420(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(1R,2S)-2-hydroxy-1,2-diphenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1-biphenyl]-4carboxylic acid, and(1S,2R)-2-amino-1,2-diphenylethanol, the title compound was obtained in73% purity by HPLC. MS(ESI+): m/z=562.

Example 421(2RS)-2-[({(2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]pyrrolidinyl}carbonyl)amino]-3-phenylpropanoicacid

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and DL-phenylalanine,the title compound was obtained in 62% purity by HPLC. MS(ESI+):m/z=500.

Example 422(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and(1S,2R)-2-aminocyclohexanecarboxamide, the title compound was obtainedin 92% purity by HPLC. MS(ESI+): m/z=491.

Example 423(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]4-carboxylic acid, and(1S,2R)-2-aminocyclohexanecarboxamide, the title compound was obtainedin 91% purity by HPLC. MS(ESI+): m/z=491.

Example 4244′-{[(2S,4EZ)-2-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-4-(methoxyimino)pyrrolidinyl]carbonyl}[1,1′-biphenyl]-2-carbonitrile

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-cyano[1,1′-biphenyl]-4-carboxylic acid, and2-(1-piperazinyl)ethanol, the title compound was obtained in 89% purityby HPLC. MS(ESI+): m/z=476.

Example 425(3EZ,5S)-1-(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl]-1-piperazinyl]carbonyl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 3′,4′-dichloro[1,1′-biphenyl]-4-carboxylic acid, and2-(1-piperazinyl)ethanol, the title compound was obtained in 86% purityby HPLC. MS(ESI+): m/z=520.

Example 426(3EZ,5S)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-5-{4-(2hydroxyethyl)-1-piperazinyl]carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and2-(1-piperazinyl)ethanol, the title compound was obtained in 79% purityby HPLC. MS(ESI+): m/z=479.

Example 427 (3EZ,5S)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]4-carboxylic acid, and2-(1-piperazinyl)ethanol, the title compound was obtained in 86% purityby HPLC. MS(ESI+): m/z=479.

Example 428(3EZ,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-({4-[4-(trifluoromethyl)phenyl]-1-piperazinyl}carbonyl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]4-carboxylic acid, and1-[4-(trifluoromethyl)phenyl]piperazine, the title compound was obtainedin 89% purity by HPLC. MS(ESI+): m/z=565.

Example 429(3EZ,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-({4-[3-(trifluoromethyl)phenyl]-1piperazinyl}carbonyl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and1-[3-(trifluoromethyl)phenyl]piperazine, the title compound was obtainedin 88% purity by HPLC. MS(ESI+): m/z=565.

Example 430(2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]carboxylic acid, and ammonia (0.5M indioxane), the title compound was obtained in 88% purity by HPLC.MS(ESI+): m/z=352.

Example 431(2S,4EZ)-4-(methoxyimino)-N-methyl-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and methylamine (2M inmethanol), the title compound was obtained in 96% purity by HPLC.MS(ESI+): m/z=366.

Example 432(2S,4EZ)-4-(methoxyimino)-N,N-dimethyl-1[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and dimethylamine(5.6M in ethanol), the title compound was obtained in 94% purity byHPLC. MS(ESI+): m/z=380.

Example 433(2S,4EZ)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1R)-3-amino-1-phenyl-1-propanol, the title compound was obtained in 94%purity by HPLC. MS(ESI+): m/z=486.

Example 434(2S,4EZ)-N-[(3S)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1S)-3-amino-1-phenyl-1-propanol, the title compound was obtained in 91%purity by HPLC. MS(ESI+): m/z=486.

Example 435(2S,4EZ)-1-([1,1′-biphenyl]4-ylcarbonyl)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]4carbonyl chloride, and(1R)-3-amino-1-phenyl-1-propanol, the title compound was obtained in 94%purity by HPLC. MS(ESI+): m/z=472.

Example 436(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(3S)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1S)-3-amino-1-phenyl-1-propanol, the title compound was obtained in 93%purity by HPLC. MS(ESI+): m/z=472.

Example 437(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2′-(trifluoromethyl)[1,1′-biphenyl]-yl]carbonyl}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid, and(1S)-2-amino-1-phenylethanol, the title compound was obtained in 87%purity by HPLC. MS(ESI+): m/z=526.

Example 438(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2′-chloro[1,1′-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-chloro[1,1′-biphenyl]-4-carboxylic acid, and(1S)2-amino-1-phenylethanol, the title compound was obtained in 89%purity by HPLC. MS(ESI+): m/z=492.

Example 439(2S,4EZ)-N-(2-hydroxyphenyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2-aminophenol, thetitle compound was obtained in 88% purity by HPLC. MS(ESI+): m/z=444.

Example 440(2S,4EZ)-N-[2-hydroxymethyl)phenyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(2-aminophenyl)methanol, the title compound was obtained in 86% purityby HPLC. MS(ESI+): m/z=458.

Example 441(2S,4EZ)-N-[(2S)-2-hydroxy-2-[phenylethyl]-4-(methoxyimino)-1-[(2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1S)-2-amino-1-phenylethanol, the title compound was obtained in 95%purity by HPLC. MS(ESI+): m/z=472.

Example 442 (2S,4E and4Z)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1S)-2-amino-1-phenylethanol, the title compounds were obtained as amixture of E/Z-isomers of the oxime functionality. Separation of theisomers by flash chromatography yielded(2S,4E)-1-([1,1′biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenyl]-4-(methoxyimino)-2-pyrrolidinecarboxamidein 98.8% purity and(2S,4Z)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2phenylethyl]-4-(methoxyimino)-2pyrrolidinecarboxamidein 97.4% purity by HPLC. MS(ESI+): m/z=458.

Example 443(2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-phenylethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2-phenylethanamine,the title compound was obtained in 89% purity by HPLC. MS(ESI+):m/z=456.

Example 444(2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-1-nonanoyl-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, nonanoic acid, and 2-aminoethanol, the title compound was obtainedin 93% purity by HPLC. MS(ESI+): m/z=342.

Example 445 Preparation of a Pharmaceutical Formulation

The following formulation examples illustrate representativepharmaceutical compositions of this invention containing pyrrolidinederivatives according to formula I. The present invention, however, isnot limited to the following pharmaceutical compositions.

Formulation 1—Tablets

A compound of formula I is admixed as a dry powder with a dry gelatinbinder in an approximate 1:2 weight ration. A minor amount of magnesiumstearate is added as a lubricant. The mixture is formed into 240–270 mgtablets (80–90 mg of active pyrrolidine derivatives according to formulaI per tablet) in a tablet press.

Formulation 2—Capsules

A compound of formula I is admixed as a dry powder with a starch diluentin an approximate 1:1 weight ratio. The mixture is filled into 250 mgcapsules (125 mg of active pyrrolidine derivatives according to formulaI per capsule).

Formulation 3—Liquid

A compound of formula I (1250 mg), sucrose (1.75 g) and xanthan gum (4mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixedwith a previously made solution of microcrystalline cellulose and sodiumcarboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10mg), flavor, and color are diluted with water and added with stirring.Sufficient water is then added to produce a total volume of 5 mL.

Formulation 4—Tablets

The compound of formula I is admixed as a dry powder with a dry gelatinbinder in an approximate 1:2 weight ratio. A minor amount of magnesiumstearate is added as a lubricant. The mixture is formed into 450–900 mgtablets (150–300 mg of active pyrrolidine derivatives according toformula I) in a tablet press.

Formulation 5—Injection

The compound of formula I is dissolved in a buffered sterile salineinjectable aqueous medium to a concentration of approximately 5 mg/ml.

The compounds of the present invention may be subjected to the followingbiological assays:

Example 446 Biological Assays

a) Production of Recombinant Bax

Human Bax-α lacking 20 amino acids at the COOH-terminus is expressed asa GST fusion protein or a His-tagged protein in Escherichia coli, andthe protein is purified from the soluble cell fraction. In brief, theGST-Bax fusion protein is applied to a glutathione-Sepharose column, andBax was released by cleavage with thrombin (0.6 U/mL). Bax issubsequently purified on heparin-Sepharose, followed by fast proteinliquid chromatography (FPLC) Mono Q. His-tagged Bax is purified on aNi-nitriloacetic acid-agarose column followed by FPLC MonoQ:

b) Isolation of Mitochondria

Mitochondria are isolated from mouse liver cells by differentialcentrifugation. Cells are broken with a dounce homogenizer and thesuspension is centrifuged at 2,000 g in an Eppendorf centrifuge at 4° C.This procedure is repeated until almost all the cells are broken. 20Supernatants from each step are pooled before centrifugation at 13,000 gat 4° C. for 10 min. The pellet is resuspended in 40 mL MB buffer andcentrifuged at 2000 g for 2 min. The supernatant is removed andcentrifuged at 13 kg for 4 min. The mitochondria are recovered in the 13k pellet and resuspended in MB buffer at a density of 30 OD600 nm/mL.

c) In Vitro Assay for Cytochrome c Release

Mitochondria (30 μg) from mouse liver are incubated with 200 nMrecombinant Bax in the presence of various compounds (5 μM) in 200 mL ofKCl buffer for 20 min at 30° C. and are then centrifuged for 4 min at13,000 g at 4° C. Mitochondrial pellets corresponding to 1.5 μg proteinsare separated by SDS-PAGE using 4–20% Tris-Gly gels (NOVEX) and theirrespective contents of cytochrome c are estimated by Western blottingusing polyclonal anti-cytochrome c antibody (dilution 1:2,500).Antigen-antibody complexes are detected using horseradishperoxidase-conjugated goat anti-rabbit IgG and enhance chemiluminescencedetection reagents. The cytochrome c bands are scanned and quantifiedusing a Bio-Rad (GS-700 Imaging Densitometer).

d) Effect of Compounds according to formula I onto the Release ofCytochrome c Trig-gered by Bid-Induced Bax Activation (In Vitro Assay)

Concerning the Bid-induced activation of Bax leading to mitochondrialCytochrome C release, it is referred to the description of Martinou etal. in The Journal of Cell Biology, Vol. 144, No. 5, Mar. 8, 1999, pages891–901. Mitochondria isolated from HeLa cells are incubated for 15 minat 30° C. in 100 μl of KCl buffer in the presence or absence of 10 nMrecombinant Bid. The various compounds (10 μM) are pre-incubated for 5min prior to addition of Bid. Following incubation, mitochondria werecentrifuged for 5 min at 13000 g at 4° C. and the supernatant iscollected for cytochrome c analysis. Cytochrome c is detected by Westernblotting. The cytochrome c bands are scanned and quantified using aBio-Rad (GS-700 Imaging Densitometer).

The above set out 2 in vitro assays c) and d) involving thedetermination of mitochondrial cytochrome c release are based onimmunochemical methods using the Western blot analysis. Alternatively,said quantitative cytochrome c determinations may be performed by usingspectrophotometric means:

-   I. by recording the difference between reduced and oxidised    cytochrome c by dual wavelength double beam spectrophotometry;-   II. by measuring the rather intensive γ or Soret peak in the    spectrum of cytochrome c (ε=100 mM⁻¹cm⁻¹) is used for rapid and    quantitative determination of the release of cytochrome c from    isolated mitochondria This technique allows a highly convenient,    fast and reliable quantitative determination of the release of    cytochrome c.    e) Sympathetic Neuron Culture and Survival Assay (in vivo assay)

Sympathetic neurons from superior cervical ganglia (SCG) of newborn rats(p4) are dis-sociated in dispase, plated at a density of 104 cells/cm²in 48 well MTT plates coated with rat tail collagen, and cultured inLeibowitz medium containing 5% rat serum, 0.75 g/ml NGF 7S (BoehringerMannheim Corp., Indianapolis, Ind.) and arabinosine 105M. Cell death isinduced at day 4 after plating by exposing the culture to mediumcontaining 10 g/ml of anti NGF antibody (Boehringer Mannheim Corp.,Indianapolis, Ind.) and no NGF or arabinosine, in the presence orabsence of pyrrolidine derivatives inhibitors according to formula I. 24hours after cell death induction, determination of cell viability isperformed by incubation of the culture for 1 hour, at 37° C. in 0.5mg/ml of 3-(4,5-dimethyl-thiazol-2-yl)-2,5 diphenyl tetrazolium bromide(MTT). After incubation in MTT cells are re-suspended in DMSO,transferred to a 96 MTT plate and cell viability is evaluated bymeas-uring optical density at 590 nm.

f) Biological Results—Discussion

By using for instance compounds

-   -   (4EZ)-N²-(2-hydroxyethyl)-4-(methoxyimino)-N¹-pentyl-1,2-pyrrolidinedicarboxamide        or    -   (2S,4EZ)-2-{[4(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]carbonyl}-4-(methoxyimino)-N-pentyl-1-pyrrolidinecarboxamide        (compound of Example 28)        at a concentration of 10 μM in the above assay d) (Effect of        Compounds according to formula I onto the Release of Cytochrome        c Triggered by Bid-Induced Bax Activation), an inhibition of        about 79% and 59% respectively was determined.

According to a preferred embodiment the tested compounds of formula Idisplay an inhibition of the cytochrome c release of at least 40%, morepreferred of at least 60% when tested at a concentration of between 2–50μM, preferably between 5–20 μM and most preferred at 5–10 μM.

1. Pyrrolidine derivatives according to formula I

as well as its geometrical isomers, its optically active forms asenantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts thereof, wherein X is selected fromthe group consisting of O, S, CR⁶R⁷,; A is selected from the groupconsisting of —(C═O)—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, and —CH₂—, B isa group —(C═O)—NR⁸R⁹ R¹ is selected from the group consisting ofunsubstituted or substituted C₁–C₆-alkyl, unsubstituted or substitutedC₂–C₆-alkenyl, unsubstituted or substituted C₂–C₆-alkynyl, unsubstitutedor substituted aryl, unsubstituted or substituted heteroaryl,unsubstituted or substituted saturated or unsaturated 3–8-memberedcycloalkyl, acyl, unsubstituted or substituted C₁–C₆-alkyl aryl, andunsubstituted or substituted C₁–C₆-alkyl heteroaryl, wherein saidcycloalkyl or aryl or heteroaryl groups may be fused with 1–2 furthercycloalkyl or aryl or heteroaryl group; R², R³, R⁴ and R⁵ areindependently selected from each other from the group consisting ofhydrogen, halogen, C₁–C₆-alkyl, and C₁–C₆-alkoxy; R⁶ and R⁷ areindependently selected from the group consisting of hydrogen,unsubstituted or substituted C₁–C₆ alkyl, unsubstituted or substitutedC₂–C₆ alkenyl, unsubstituted or substituted C₂–C₆ alkynyl, unsubstitutedor substituted alkoxy, unsubstituted or substituted thioalkoxy, halogen,cyano, nitro, acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted orsubstituted saturated or unsaturated 3–8-membered cycloalkyl which maycontain 1 to 3 heteroatoms selected of N, O, S, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted C₁–C₆-alkyl aryl, and unsubstituted or substitutedC₁–C₆-alkyl heteroaryl; R⁸, R⁹ are independently selected from the groupconsisting of hydrogen, unsubstituted or substituted C₁–C₆ alkyl,unsubstituted or substituted C₂–C₆ alkenyl, unsubstituted or substitutedC₂–C₆ alkynyl, unsubstituted or substituted saturated or unsaturated3–8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected ofN, O, S, unsubstituted or substituted aryl, and unsubstituted orsubstituted heteroaryl, or each pair R⁶, R⁷ and/or R⁸, R⁹ may formtogether with the N atom to which they are attached a 3–8 memberedsubstituted or unsubstituted, saturated or unsaturated hetero-cyclicring which may contain 1–2 further heteroatoms selected from N, S and Oand which is optionally fused with an aryl, heteroaryl or 3–8 memberedsaturated or unsaturated cycloalkyl ring; with the proviso that thefollowing compounds are excluded:


2. A pyrrolidine derivative according to claim 1, wherein B is a group—(C═O)—NHR⁹, in which R⁹ is selected from the group consisting ofunsubstituted or substituted C_(1–C) ₆ alkyl, unsubstituted orsubstituted C₂–C₆ alkenyl, unsubstituted or substituted C₂–C₆ alkynyl,unsubstituted or substituted saturated or unsaturated 3–6-memberedcycloalkyl which optionally contains a N atom, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted C₁–C₂-alkyl aryl, and unsubstituted or substitutedC₁–C₂-alkyl heteroaryl.
 3. A pyrrolidine derivative according to claim2, wherein R⁹ is a heteroaryl selected from the group consisting ofpyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothia-zolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl,isobenzo-thienyl, 2,1,3-benzothiadiazolyl, 2,1,3-benzoxadiazolyl,benzodioxolyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl,quinazolinyl, phthalazinyl, quinoxalinyl, cinnnolinyl, napthyridinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,xanthenyl, acridinyl and benzoquinolyl and whereby said heteroaryl canbe fused with a 3–8-membered cycloalkyl containing optionally 1–3heteroatoms selected from N, O, S.
 4. A pyrrolidine derivative accordingto any of claim 1, 2 or 3, wherein X is CHR⁶, R⁶ is selected from thegroup consisting of halogen, cyano, unsubstituted or substituted C₃–C₆alkyl, unsubstituted or substituted C₂–C₆ alkenyl, unsubstituted orsubstituted C₂–C₆ alkynyl, unsubstituted or substituted alkoxy,unsubstituted or substituted thioalkoxy, nitro, acyl, alkoxycarbonyl,aminocarbonyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl, unsubstituted or substituted saturated orunsaturated 3–8-membered cycloalkyl, unsubstituted or substitutedC₁–C₆-alkyl aryl, and unsubstituted or substituted C₁–C₆-alkylheteroaryl, wherein said cycloalkyl or aryl or heteroaryl groups may befused with 1–2 further cycloalkyl or aryl or heteroaryl groups.
 5. Apyrrolidine derivative according to claim 4, wherein R⁶ is selected fromthe group consisting of halogen, cyano, and C₃–C₆ alkyl or anunsubstituted or substituted phenyl group.
 6. A pyrrolidine derivativeaccording to any of claim 1, 2 or 3, wherein X is O.
 7. A pyrrolidinederivative according to claim 1, wherein A is —(C═O)—, or —(C═O)—NH—. 8.A pyrrolidine derivative according to claim 7, wherein A is —(C═O)—. 9.A pyrrolidine derivative according to claim 1, wherein R¹ is selectedfrom the group consisting of an C₆–C₆-alkyl, C₂–C₆-alkenyl,unsubstituted or substituted C₂–C₆-alkynyl, aryl, heteroaryl, saturatedor unsaturated 3–8-mastered cycloalkyl, C₁–C₆-alkyl aryl, andC₁–C₆-alkyl heteroaryl.
 10. A pyrrolidine derivative according to claim9, wherein R¹ is an C₁–C₆-alkyl or aryl group.
 11. A pyrrolidinederivative according to claim 10, wherein R¹ is biphenyl.
 12. Apyrrolidine derivative according to claim 1, wherein X is ═CHCl, B is anamido group of the formula —(C═O)NHR⁹), wherein R⁹ is as above defined,A is C═O and R¹ is a C₁–C₆-alkyl-aryl, an aryl or a C₁–C₆-alkyl group.13. A pyrrolidine derivative according to claim 12, wherein X is either═CH—Cl, B is an amido group of the formula —(C═O)NHR⁹), wherein a R⁹ isa C₁–C₆-alkyl-aryl, an aryl, a C₁–C₆-alkyl which is substituted by aprimary, secondary or tertiary amine, A is C═O and R¹ is a diphenylmethyl or a phenyl group.
 14. A pyrrolidine derivative according toclaim 1 selected from the group consisting of:(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-hydroxy-2-phenyl-ethyl)-2-pyrrolidinecarboxamide;(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-furylmethyl)-2-pyrrolidinecarboxamide;(2S,4EZ)-1-[(4-chlorophenoxy)acetyl]-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide;(2S,4EZ)-4-(cyanomethylene)-N-(2-furylmethyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide;(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-4-(cyanomethylene)-1-(diphenylacetyl)-2-pyrrolidinecarboxamide;(2S)-2-[1-([1,1′-biphenyl]-4-ylcarbonyl)-4-methylene-2-pyrrolidinyl]-1H-benzimidazole;(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-((2-methoxyethyl)-2-pyrrolidinecarboxamide;(2S,4EZ)-4-(chloromethylene)-1-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide;(2S)1([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-methylene-2-pyrrolidinecarboxamide;(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide;(2S,4EZ)-4-benzylidene-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-2-pyrrolidinecarboxamide;(2S,4EZ)-4-(chloromethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide;(2S)-N-(2-furylmethyl)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide;(2S)-1-(1,1′-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-methylene-2-pyrrolidinecarboxamide;(2S,4EZ)-4-(cyanomethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide;(2S)-1-(diphenylacetyl)-N-(1-naphthylmethyl)-4-oxo-2-pyrrolidinecarboxamide;(2S)-N1-(3,5-dichlorophenyl)-N2-(3,4-dimethoxybenzyl)-4-oxo-1,2-pyrrolidine-dicarboxamide;and(2S)-4-oxo-1-(phenoxyacetyl)-N-[2-(1H-pyrrol-1-yl)phenyl]-2-pyrrolidinecarboxamide.15. A composition comprising a carrier and a pyrrolidine derivativeaccording to claim 1, with the proviso that the following compounds areexcluded from the composition


16. A pharmaceutical composition containing at least one pyrrolidinederivative according to claim 1 and a pharmaceutically acceptablecarrier, diluent or excipient thereof.
 17. A process for the preparationof a pyrrolidine derivative according to claim 1, wherein the followingreaction is performed:

whereby LG is a leaving group and the substituents R¹–R⁹, A and X are asabove defined.
 18. A method for treating a neuronal disorder, comprisingadministering to a patient in need thereof a pyrrolidine derivativeaccording to formula IA

as well as its geometrical isomers, its optically active forms asenantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts thereof, wherein X is selected fromthe group consisting of O, S, CR⁶R⁷, NOR⁶, and NNR⁶R⁷; A is selectedfrom the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—,—(C═S)—NH, —SO₂—, —SO₂NH—, and —CH₂—, R¹ is selected from the groupconsisting of unsubstituted or substituted C_(1–C) ₆-alkyl,unsubstituted or substituted C₂–C₆-alkenyl, unsubstituted or substitutedC₂–C₆-alkynyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl, unsubstituted or substituted saturated orunsaturated 3–8-membered cycloalkyl, acyl, unsubstituted or substitutedC₁–C₆-alkyl aryl, and unsubstituted or substituted C₁–C₆-alkylheteroaryl, wherein said cycloalkyl or aryl or heteroaryl groups may befused with 1–2 further cycloalkyl or aryl or heteroaryl group; R², R³,R⁴ and R⁵ are independently selected from each other from the groupconsisting of hydrogen, halogen, C₁–C₆-alkyl, and C₁–C₆-alkoxy; R⁶ andR⁷ are independently selected from the group consisting of hydrogen,unsubstituted or substituted C₁–C₆ alkyl, unsubstituted or substitutedC₂–C₆ alkenyl, unsubstituted or substituted C₂–C₆ alkynyl, unsubstitutedor substituted alkoxy, unsubstituted or substituted thioalkoxy, halogen,cyano, nitro, acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted orsubstituted saturated or unsaturated 3–8-membered cycloalkyl which maycontain 1 to 3 heteroatoms selected of N, O, S, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted C₁–C₆-alkyl aryl, and unsubstituted or substitutedC₁–C₆-alkyl heteroaryl; R⁸, R⁹ are independently selected from the groupconsisting of hydrogen, unsubstituted or substituted C₁–C₆ alkyl,unsubstituted or substituted C₂–C₆ alkenyl, unsubstituted or substitutedC₂–C₆ alkynyl, unsubstituted or substituted saturated or unsaturated3–8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected ofN, O, S, unsubstituted or substituted aryl, and unsubstituted orsubstituted heteroaryl, or each pair R⁶, R⁷ and/or R⁸, R⁹ can formtogether with the N atom to which they are attached a 3–8 memberedsubstituted or unsubstituted, saturated or unsaturated hetero-cyclicring which may contain 1–2 further heteroatoms selected from N, S and Oand which is optionally fused with an aryl, heteroaryl or 3–8 memberedsaturated or unsaturated cycloalkyl ring; R¹¹ is selected from the groupconsisting of hydrogen, unsubstituted or substituted C₁–C₆-alkyl,unsubstituted or substituted alkenyl, unsubstituted or substitutedalkynyl, hydroxy, mercapto, alkoxy, thioalkoxy, aryl, heteroaryl,halogen, nitro, cyano, acyl, acyloxy, acylamino, aminocarbonyl,alkoxycarbonyl, sulfonyl, sulfoxy, carboxyl, primary, secondary ortertiary amino groups or quarternary ammonium moieties, andunsubstituted or substituted saturated or unsaturated 3–8-memberedcycloalkyl.
 19. A method according to claim 18, wherein the neuronaldisorder is selected from the group consisting of epilepsy, Alzheimer'sdisease, Huntington's disease, Parkinson's disease, retinal diseases,spinal cord injury, Crohn's disease, head trauma, spinocerebellarataxias, and dentatorubral-pallidoluysian atrophy.
 20. A methodaccording to claim 18, wherein said administering step administers thepharmaceutical composition orally to the patient.
 21. A method fortreating an autoimmune disease, comprising administering to a patient inneed thereof a pyrrolidine derivative according to Formula IA

as well as its geometrical isomers, its optically active forms asenantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts thereof, wherein X is selected fromthe group consisting of O, S, CR⁶R⁷, NOR⁶, and NNR⁶R⁷; A is selectedfrom the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—,—(C═S)—NH, —SO₂—, —SO₂NH—, and —CH₂—, R¹ is selected from the groupconsisting of unsubstituted or substituted C₁–C₆-alkyl, unsubstituted orsubstituted C₂–C₆-alkenyl, unsubstituted or substituted C₂–C₆-alkynyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted saturated or unsaturated3–8-membered cycloalkyl, acyl, unsubstituted or substituted C₁–C₆-alkylaryl, and unsubstituted or substituted C₁–C₆-alkyl heteroaryl, saidcycloalkyl or aryl or heteroaryl groups may be fused with 1–2 furthercycloalkyl or aryl or heteroaryl group; R², R³, R⁴ and are R⁵independently selected from each other from the group consisting ofhydrogen, halogen, C₁–C₆-alkyl, and C₁–C₆-alkoxy; R⁶ and R⁷ areindependently selected from the group consisting of hydrogen,unsubstituted or substituted C₂–C₆ alkyl, unsubstituted or substitutedC₂–C₆ alkenyl, unsubstituted or substituted C₂–C₆ alkynyl, unsubstitutedor substituted alkoxy, unsubstituted or substituted thioalkoxy, halogen,cyano, nitro, acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted orsubstituted saturated or unsaturated 3–8-membered cycloalkyl which maycontain 1 to 3 heteroatoms selected of N, O, S, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted C₁–C₆-alkyl aryl, and unsubstituted or substitutedC₁–C₆-alkyl heteroaryl; R⁸, R⁹ are independently selected from the groupconsisting of hydrogen, unsubstituted or substituted C_(1–C) ₆ alkyl,unsubstituted or substituted C₂–C₆ alkenyl, unsubstituted or substitutedC₂–C₆ alkynyl, unsubstituted or substituted saturated or unsaturated3–8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected ofN, O, S, unsubstituted or substituted aryl, and unsubstituted orsubstituted heteroaryl, or each pair R⁶, R⁷ and/or R⁸, R⁹ can formtogether with the N atom to which they are attached a 3–8 memberedsubstituted or unsubstituted, saturated or unsaturated heterocyclic ringwhich may contain 1–2 further heteroatoms selected from N, S and O andwhich is optionally fused with an aryl, heteroaryl or 3–8 memberedsaturated or unsaturated cycloalkyl ring; R¹¹ is selected from the groupconsisting of hydrogen, unsubstituted or substituted C₁–C₆-alkyl,unsubstituted or substituted alkenyl, unsubstituted or substitutedalkynyl, hydroxy, mercapto, alkoxy, thioalkoxy, aryl, heteroaryl,halogen, nitro, cyano, acyl, acyloxy, acylamino, aminocarbonyl,alkoxycarbonyl, sulfonyl, sulfoxy, carboxyl, primary, secondary ortertiary amino groups or quarternary ammonium moieties, andunsubstituted or substituted saturated or unsaturated 3–8-memberedcycloalkyl.
 22. A method according to claim 21, wherein the autoimmunedisease is selected from the group consisting of Multiple Sclerosis,amyotrophic lateral sclerosis, retinitis pigmentosa, inflammatory boweldisease (IBD), rheumatoid arthritis, asthma, septic shock, transplantrejection, and AIDS.
 23. A method according to claim 21, wherein saidadministering step administers the pharmaceutical composition orally tothe patient.
 24. A method for treating ischemia, comprisingadministering to a patient in need thereof a pyrrolidine derivativeaccording to formula I

as well as its geometrical isomers, its optically active forms asenantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts thereof, wherein X is selected fromthe group consisting of O, S, CR⁶R⁷, NOR⁶, and NNR⁶R⁷; A is selectedfrom the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—,—(C═S)—NH, —SO₂—, —SO₂NH—, and —CH₂—, B is a group —(C═O)—NR⁸R⁹; R¹ isselected from the group consisting of unsubstituted or substitutedC₁–C₆-alkyl, unsubstituted or substituted C₂–C₆-alkenyl, unsubstitutedor substituted C₂–C₆-alkynyl, unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl, unsubstituted or substitutedsaturated or unsaturated 3–8-membered cycloalkyl, acyl, unsubstituted orsubstituted C₁–C₆-alkyl aryl, and unsubstituted or substitutedC₁–C₆-alkyl heteroaryl, wherein said cycloalkyl or aryl or heteroarylgroups may be fused with 1–2 further cycloalkyl or aryl or heteroarylgroup; R², R³, R⁴ and R⁵ are independently selected from each other fromthe group consisting of hydrogen, halogen, C₁–C₆-alkyl, andC₁–C₆-alkoxy; R⁶ and R⁷ are independently selected from the groupconsisting of hydrogen, unsubstituted or substituted C₁–C₆ alkyl,unsubstituted or substituted C₂–C₆ alkenyl, unsubstituted or substitutedC₂–C₆ alkynyl, unsubstituted or substituted alkoxy, unsubstituted orsubstituted thioalkoxy, halogen, cyano, nitro, acyl, alkoxycarbonyl,aminocarbonyl, unsubstituted or substituted saturated or unsaturated3–8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected ofN, O, S, unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted C₁–C₆-alkyl aryl, andunsubstituted or substituted C₁–C₆-alkyl heteroaryl; R⁸, R⁹ areindependently selected from the group consisting of hydrogen,unsubstituted or substituted C₁–C₆ alkyl, unsubstituted or substitutedC₂–C₆ alkenyl, unsubstituted or substituted C₂–C₆ alkynyl, andunsubstituted or substituted saturated or unsaturated 3–8-memberedcycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, or each pair R⁶, R⁷ and/or R⁸, R⁹ can form together with theN atom to which they are attached a 3–8 membered substituted orunsubstituted, saturated or unsaturated hetero-cyclic ring which maycontain 1–2 further heteroatoms selected from N, S and O and which isoptionally fused with an aryl, heteroaryl or 3–8 membered saturated orunsaturated cycloalkyl ring; R¹¹ is selected from the group consistingof hydrogen, unsubstituted or substituted C₁–C₆-alkyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, hydroxy,mercapto, alkoxy, thioalkoxy, aryl, heteroaryl, halogen, nitro, cyano,acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, sulfonyl,sulfoxy, carboxyl, primary, secondary or tertiary amino groups orquarternary ammonium moieties, and unsubstituted or substitutedsaturated or unsaturated 3–8-membered cycloalkyl.
 25. A method accordingto claim 24, wherein ischemia is caused by an event selected from thegroup consisting of stroke, myocardial infarction and reperfusioninjury, cardiovascular disorders, arteriosclerosis, heart failure, hearttransplantation, renal hypoxia, and hepatitis.
 26. A method according toclaim 24, wherein said administering step administers the pharmaceuticalcomposition orally to the patient.
 27. A method for treating aninfertility related disorder, comprising administering to a patient inneed thereof a pyrrolidine derivative according to formula I

as well as its geometrical isomers, its optically active forms asenantiomers, diastereo-mers and its racemate forms, as well aspharmaceutically acceptable salts thereof, wherein X is selected fromthe group consisting of O, S, CR⁶R⁷, NOR⁶, and NNR⁶R⁷; A is selectedfrom the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—,—(C═S)—NH, —SO₂—, —SO₂NH—, and —CH₂—, B is a group —(C═O)—NR⁸R⁹; R¹ isselected from the group consisting of unsubstituted or substitutedC₁–C₆-alkyl, unsubstituted or substituted C₂–C₆-alkenyl, unsubstitutedor substituted C₂–C₆-alkynyl, unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl, unsubstituted or substitutedsaturated or unsaturated 3–8-membered cycloalkyl, acyl, unsubstituted orsubstituted C₁–C₆-alkyl aryl, and unsubstituted or substitutedC₁–C₆-alkyl heteroaryl, wherein said cycloalkyl or aryl or heteroarylgroups may be fused with 1–2 further cycloalkyl or aryl or heteroarylgroup; R², R³, R⁴ and R⁵ are independently selected from each other fromthe group consisting of hydrogen, halogen, C₁–C₆-alkyl, andC₁–C₆-alkoxy; R⁶ and R⁷ are independently selected from the groupconsisting of hydrogen, unsubstituted or substituted C₂–C₆ alkyl,unsubstituted or substituted C₂–C₆ alkenyl, unsubstituted or substitutedC₂–C₆ alkynyl, unsubstituted or substituted alkoxy, unsubstituted orsubstituted thioalkoxy, halogen, cyano, nitro, acyl, alkoxycarbonyl,aminocarbonyl, unsubstituted or substituted saturated or unsaturated3–8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected ofN, O, S, unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted C₁–C₆-alkyl aryl, andunsubstituted or substituted C₁–C₆-alkyl heteroaryl; R⁸, R⁹ areindependently selected from the group consisting of hydrogen,unsubstituted or substituted C₁–C₆ alkyl, unsubstituted or substitutedC₂–C₆ alkenyl, unsubstituted or substituted C₂–C₆ alkynyl, unsubstitutedor substituted saturated or unsaturated 3–8-membered cycloalkyl whichmay contain 1 to 3 heteroatoms selected of N, O, S, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl, or eachpair R⁶, R⁷ and/or R⁸, R⁹ can form together with the N atom to whichthey are attached a 3–8 membered substituted or unsubstituted, saturatedor unsaturated hetero-cyclic ring which may contain 1–2 furtherheteroatoms selected from N, S and O and which is optionally fused withan aryl, heteroaryl or 3–8 membered saturated or unsaturated cycloalkylring; R¹¹ is selected from the group consisting of hydrogen,unsubstituted or substituted C₁–C₆-alkyl, unsubstituted or substitutedalkenyl, unsubstituted or substituted alkynyl, hydroxy, mercapto,alkoxy, thioalkoxy, aryl, heteroaryl, halogen, nitro, cyano, acyl,acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, sulfonyl, sulfoxy,carboxyl, primary, secondary or tertiary amino groups or quarternaryammonium moieties, and unsubstituted or substituted saturated orunsaturated 3–8-membered cycloalkyl.
 28. A method according to claim 27,wherein the infertility related disorder is selected from the groupconsisting of premature menopause, ovarian failure, and follicularatresia.
 29. A method according to claim 27, wherein said administeringstep administers the pharmaceutical composition orally to the patient.